List of phenyltropanes

From Wikipedia the free encyclopedia

Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function.[a] These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's & Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.[2]) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article)[b] Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds.
Troparil structure: c.f. U.S. patent 5,496,953

2-Carboxymethyl esters (phenyl-methylecgonines)[edit]

Epibatropane[3] containing a nitrogen heteroatom in the benzene ring formation.
Tamagnan:[4] SSRI, SERT = 17(pM) = 10 times the strength of paroxetine for 5HT.
RTI-298
(4′-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (>2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity.
C2-C3 unsaturated (non-isomeric, neither α nor β orientated) 2-naphthyl-tropane
1-naphthyl-tropane in its usual (comparably non-standard) boat formation of its tropane ring.

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.[5]

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.[c] The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.[d]

Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes (IC50 values)
monohalogen halide-phenyltropanes (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z)
Structure Short Name
i.e. Trivial IUPAC
(non-systematic) Name
(Singh's #) 		R (para-substitution)
of benzene 		DA
[3H]WIN 35428
IC50 nM
(Ki nM) 		5HT
[3H]paroxetine
IC50 nM
(Ki nM) 		NE
[3H]nisoxetine
IC50 nM
(Ki nM) 		selectivity
5-HTT/DAT 		selectivity
NET/DAT
cocaine
(benzoyloxytropane)		 H 102 ± 12
241 ± 18ɑ		 1045 ± 89
112 ± 2b		 3298 ± 293
160 ± 15c		 10.2
0.5d		 32.3
0.7e
(para-hydrogen)phenyltropane
WIN 35,065-2 (β-CPT[e]) Troparil
11a		 H 23 ± 5.0
49.8 ± 2.2ɑ		 1962 ± 61
173 ± 13b		 920 ± 73
37.2 ± 5.2c		 85.3
3.5d		 40.0
0.7e
para-fluorophenyltropane
WIN 35,428 (β-CFT[f])
11b		 F 14 (15.7 ± 1.4)
22.9 ± 0.4ɑ		 156 (810 ± 59)
100 ± 13b		 85 (835 ± 45)
38.6 ± 9.9c		 51.6
4.4d		 53.2
1.7e
para-nitrophenyltropane
11k		 NO2 10.1 ± 0.10 ? ? ? ?
para-aminophenyltropane
RTI-29[6]
11j		 NH2 9.8
24.8 ± 1.3g		 5110 151 521.4 15.4
para-chlorophenyltropane
RTI-31
11c		 Cl 1.12 ± 0.06
3.68 ± 0.09ɑ		 44.5 ± 1.3
5.00 ± 0.05b		 37 ± 2.1
5.86 ± 0.67c		 39.7
1.3d		 33.0
1.7e
para-methylphenyltropane
RTI-32 Tolpane
11f		 Me 1.71 ± 0.30
7.02 ± 0.30ɑ		 240 ± 27
19.38 ± 0.65b		 60 ± 0.53e
8.42 ± 1.53c		 140
2.8d		 35.1
1.2e
para-bromophenyltropane
RTI-51 Bromopane
11d		 Br 1.81 (1.69) ± 0.30 10.6 ± 0.24 37.4 ± 5.2 5.8 20.7
para-iodophenyltropane
RTI-55 (β-CIT) Iometopane
11e		 I 1.26 ± 0.04
1.96 ± 0.09ɑ		 4.21 ± 0.3
1.74 ± 0.23b		 36 ± 2.7
7.51 ± 0.82c		 3.3
0.9d		 28.6
3.8e
para-hydroxyphenyltropane
11h		 OH 12.1 ± 0.86 — — — —
para-methoxyphenyltropane
11i		 OCH3 8.14 ± 1.3 — — — —
para-azidophenyltropane
11l		 N3 2.12 ± 0.13 — — — —
para-trifluoromethylphenyltropane
11m		 CF3 13.1 ± 2.2 — — — —
para-acetylaminophenyltropane
11n		 NHCOCH3 64.2 ± 2.6 — — — —
para-propionylaminophenyltropane
11o		 NHCOC2H5 121 ± 2.7 — — — —
para-ethoxycarbonylaminophenyltropane
11p		 NHCO2C3H5 316 ± 48 — — — —
para-trimethylstannylphenyltropane
11q		 Sn(CH3)3 144 ± 37 — — — —
para-ethylphenyltropane
RTI-83
11g		 Et 55 ± 2.1 28.4 ± 3.8
(2.58 ± 3.5)		 4030 (3910) ± 381
(2360 ± 230)		 0.5 73.3
para-n-propylphenyltropane
RTI-282i
11r		 n-C3H7 68.5 ± 7.1 70.4 ± 4.1 3920 ± 130 1.0 57.2
para-isopropylphenyltropane
11s		 CH(CH3)2 597 ± 52 191 ± 9.5 75000 ± 5820 0.3 126
para-vinylphenyltropane
RTI-359
11t		 CH-CH2 1.24 ± 0.2 9.5 ± 0.8 78 ± 4.1 7.7 62.9
para-methylethenylphenyltropane
RTI-283j
11u		 C(=CH2)CH3 14.4 ± 0.3 3.13 ± 0.16 1330 ± 333 0.2 92.4
para-trans-propenylphenyltropane
RTI-296i
11v		 trans-CH=CHCH3 5.29 ± 0.53 11.4 ± 0.28 1590 ± 93 2.1 300
para-allylphenyltropane
11x		 CH2CH=CH2 32.8 ± 3.1 28.4 ± 2.4 2480 ± 229 0.9 75.6
para-ethynylphenyltropane
RTI-360
11y		 C≡CH 1.2 ± 0.1 4.4 ± 0.4 83.2 ± 2.8 3.7 69.3
para-propynylphenyltropane
RTI-281i
11z		 C≡CCH3 2.37 ± 0.2 15.7 ± 1.5 820 ± 46 6.6 346
para-cis-propenylphenyltropane
RTI-304
11w		 cis-CH=CHCH3 15 ± 1.2 7.1 ± 0.71 2,800k ± 300 0.5 186.6k
para-(Z)-phenylethenylphenyltropane cis-CH=CHPh 11.7 ± 1.12 — — — —
para-benzylphenyltropane -CH2-Ph 526 ± 65 7,240 ± 390
(658 ± 35)		 6670 ± 377
(606 ± 277)		 13.7 12.6
para-phenylethenylphenyltropane CH2
║
-C-Ph		 474 ± 133 2,710 ± 800
(246 ± 73)		 7,060 ± 1,760
(4,260 ± 1,060)		 5.7 14.8
para-phenylethylphenyltropanel -(CH2)2-Ph 5.14 ± 0.63 234 ± 26
(21.3 ± 2.4)		 10.8 ± 0.3
(6.50 ± 0.20)		 45.5 2.1
para-(E)-phenylethenylphenyltropanel
RTI-436		 trans–CH=CHPh 3.09 ± 0.75 335 ± 150
(30.5 ± 13.6)		 1960 ± 383
(1180 ± 231)		 108.4 634.3
para-phenylpropylphenyltropanel -(CH2)3-Ph 351 ± 52 1,243 ± 381
(113 ± 35)		 14,200 ± 1,800
(8,500 ± 1,100)		 3.5 40.4
para-phenylpropenylphenyltropanel -CH=CH-CH2-Ph 15.8 ± 1.31 781 ± 258
(71 ± 24)		 1,250 ± 100
(759 ± 60)		 49.4 79.1
para-phenylbutylphenyltropanel -(CH2)4-Ph 228 ± 21 4,824 ± 170
(439 ± 16)		 2,310 ± 293
(1,390 ± 177)		 21.1 10.1
para-phenylethynylphenyltropanel
RTI-298[7]		 –≡–Ph 3.7 ± 0.16 46.8 ± 5.8
(4.3 ± 0.53)		 347 ± 25
(209 ± 15)		 12.6 93.7
para-phenylpropynylphenyltropanel[8] –C≡C-CH2Ph 1.82 ± 0.42 13.1 ± 1.7
(1.19 ± 0.42)		 27.4 ± 2.6
(16.5 ± 1.6)		 7.1 15
para-phenylbutynylphenyltropanel
RTI-430		 –C≡C(CH2)2Ph 6.28 ± 1.25 2180 ± 345
(198 ± 31)		 1470 ± 109
(885 ± 66)		 347.1 234
para-phenylpentynylphenyltropanel –C≡C-(CH2)3-Ph 300 ± 37 1,340 ± 232
(122 ± 21)		 4,450 ± 637
(2,680 ± 384)		 4.46 14.8
para-trimethylsilylethynylphenyltropane[3] — — — — — —
para-hydroxypropynylphenyltropane[3] — — — — — —
para-hydroxyhexynylphenyltropanel –C≡C-(CH2)4OH 57 ± 4 828 ± 29
(75 ± 2.6)		 9,500 ± 812
(5,720 ± 489)		 14.5 166.6
para-(thiophen-3-yl)phenyltropane
Tamagnan[4]		 p-thiophene 12 0.017 189 0.001416 15.7
para-biphenyltropane
11aa		 Ph 10.3 ± 2.6f
29.4 ± 3.8ɑ
15.6 ± 0.6		 95.8 ± 36
(8.7 ± 3.3)		 1,480 ± 269
(892 ± 162)		 6.1 94.8
3β-2-naphthyltropane
RTI-318
11bb		 3β-2-naphthyl 0.51 ± 0.03
3.32 ± 0.08f
3.53 ± 0.09ɑ		 0.80 ± 0.06
(0.07 ± 0.1)		 21.1 ± 1.0
(12.7 ± 0.60)		 1.5 41.3
para-bimethoxyphenyltropane
15		 OCH2OCH3h — — — — —
  • ɑ[3H]DA uptake displacement Ki value.
  • b[3H]5-HT uptake displacement Ki value.
  • c[3H]NE uptake displacement Ki value.
  • d[3H]5-HT uptake to [3H]DA uptake ratio.
  • e[3H]NE uptake to [3H]DA uptake ratio.
  • fIC50 for displacement of [3H]cocaine.
  • gValues from alternate data-set differing from that used in rest of table.
  • hOriginal source (Scheme 4, page 931, 7th of article)[1] name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: i.e. "methoxymethyl" versus "methoxymethoxy"
  • iProtonated as the (-)—tartrate salt (isomer)
  • jProtonated as the tartrate salt
  • kWas cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867. However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1[9] which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value.
  • lWhereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the para-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to a 180° extension outward from the para area of the aryl of these type of ligands.[8]

(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes[edit]

Tamagnan (thiophene) analogues of para-phenyltropanes.[4]
Compound structure Alphanumeric code
(name) 		para-substitution N8 SERT DAT NET Selectivity
SERT versus DAT 		Selectivity
SERT versus NET
1
(cocaine)		 (—)-Cocaine CH3 1050 89 3320 0.08 3.2
2
(β-CIT), (Iometopane)		 Iodo CH3 0.46 ± 0.06 0.96 ± 0.15 2.80 ± 0.40 2.1 6.1
(R,S-Citalopram) — — 1.60 16,540 6,190 10,338 3,869
4a 2-Thiophene CH3 0.15 ± 0.015 52 ± 12.8 158 ± 12 346 1,053
4b
(Tamagnan)		 3-Thiophene CH3 0.017 ± 0.004 12.1 ± 3 189 ± 82 710 11,118
4c 2-(5-Br)-Thiophene CH3 0.38 ± 0.008 6.43 ± 0.9 324 ± 19 17 853
4d 2-(5-Cl)-Thiophene CH3 0.64 ± 0.04 4.42 ± 1.64 311 ± 25 6.9 486
4e 2-(5-I)-Thiophene CH3 4.56 ± 0.84 22.1 ± 3.2 1,137 ± 123 4.9 249
4f 2-(5-NH2)-Thiophene CH3 64.7 ± 3.7 >10,000 >30,000 >155 >464
4g 2-(4,5-NO2)-Thiophene CH3 5,000 >30,000 >10,000 >6.0 >2.0
4h 3-(4-Br)-Thiophene CH3 4.02 ± 0.34 183 ± 69 >10,000 46 >2,488
5a 2-Thiophene H 0.11 ± 0.006 12.2 ± 0.9 75.3 ± 9.6 111 685
5b 3-Thiophene H 0.23 ± 0.02 6.4 ± 0.27 39 ± 0.8 28 170

(3′,4′-Disubstituted phenyl)-tropanes[edit]

Compound
(+ S. Singh's name)		 X
(4′-para)		 Y
(3′-meta)		 2 Position config 8 DA 5-HT NE
RTI-318
11bb		 β-naphthyl CO2Me β,β NMe 0.5 0.81 20
Dichloropane (RTI-111ɑ)[10]
17c		 Cl Cl CO2Me β,β NMe 0.79 3.13 18.0
RTI-88 [recheck]
17e		 NH2 I CO2Me β,β NMe 1.35 1329c 320c
RTI-97
17d		 NH2 Br CO2Me β,β NMe 3.91 181 282
RTI-112b
17b		 Cl Me CO2Me β,β NMe 0.82 10.5 36.2
RTI-96
17a		 F Me CO2Me β,β NMe 2.95 76 520
RTI-295 Et I CO2Me β,β NMe 21.3 2.96 1349
RTI-353 (EINT) Et I CO2Me β,β NH 331 0.69 148
RTI-279 Me I CO2Me β,β NH 5.98 1.06 74.3
RTI-280 Me I CO2Me β,β NMe 3.12 6.81 484
Meltzer[11] catechol CO2Me β,β NMe >100 ? ?
Meltzer[11] OAc OAc CO2Me β,β NMe ? ? ?
  • ɑas ·HCl (salt)
  • bas ·HCl·2 H2O (salt)
  • cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT
Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes[1]
Compound Short Name
(S. Singh) 		R2 R1 DA 5HT NE Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
meta-fluorophenyltropane
16a		 F H 23 ± 7.8 - - - -
meta-chlorophenyltropane
16b		 Cl H 10.6 ± 1.8 - - - -
meta-bromophenyltropane
16c		 Br H 7.93 ± 0.08ɑ - - - -
meta-iodophenyltropane
16d		 I H 26.1 ± 1.7 - - - -
meta-tributylstannylphenyltropane
16e		 SnBu3 H 1100 ± 170 - - - -
meta-ethynylphenyltropane[3] C≡CH H - - - - -
meta-methyl-para-fluorophenyltropane
RTI-96
17a		 CH3 F 2.95 ± 0.58 - - - -
meta-methyl-para-chlorophenyltropane
RTI-112c
17b		 CH3 Cl 0.81 ± 0.05 10.5 ± 0.05 36.2 ± 1.0 13.0 44.7
meta-para-dichlorophenyltropane
RTI-111b[10] Dichloropane
17c		 Cl Cl 0.79 ± 0.08b 3.13 ± 0.36b 18.0 ± 0.8
17.96 ± 0.85'b'd		 4.0b 22.8b
meta-bromo-para-aminophenyltropane
RTI-97
17d		 Br NH2 3.91 ± 0.59 181 282 46.2 72.1
meta-iodo-para-aminophenyltropane
RTI-88
17e		 I NH2 1.35 ± 0.11 120 ± 4 1329 ± 124 88.9 984
meta-iodo-para-azidophenyltropane
17f		 I N3 4.93 ± 0.32 - - - -
3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropanes[12]
Structure Compound R X n Inhibition of [3H]WIN 35,428
@ DAT
IC50 (nM) 		Inhibition of [3H]Paroxetine
@ 5-HTT
Ki (nM) 		Inhibition of [3H]Nisoxetine
@ NET
Ki (nM) 		NET/DAT
(uptake ratio) 		NET/5-HTT
(uptake ratio)
Cocaine Des-thio/sulfinyl/sulfonyl
H		 H Desmethyl
0		 89.1 95 1990 22 21
para-methoxyphenyltropane
Singh: 11i		 Des-thio/sulfinyl/sulfonyl
OCH3		 H 0 6.5 ± 1.3 4.3 ± 0.5 1110 ± 64 171 258
7a CH3 H 0 9 ± 3 0.7 ± 0.2 220 ± 10 24 314
7b C2H5 H 0 232 ± 34 4.5 ± 0.5 1170 ± 300 5 260
7c CH(CH3)2 H 0 16 ± 2 23 ± 2 129 ± 2 8 7
7d CF3 H 0 200 ± 70 8 ± 2 1900 ± 300 10 238
7e CH3 Br 0 10.1 ± 1 0.6 ± 0.2 121 ± 12 12 202
7f CH3 Br 1 76 ± 18 3.2 ± 0.4 690 ± 80 9 216
7g CH3 H 1 91 ± 16 4.3 ± 0.6 515 ± 60 6 120
7h CH3 H 2 >10,000 208 ± 45 >10,000 1 48

(2′,4′-Disubstituted phenyl)-tropanes[edit]

Ortho-para-substituted (2′,4′-disubstituted phenyltropanes)
Compound structure
 Trivial IUPAC
(non-systematic)
Name 		R2
ortho 		R1
para 		DA 5HT NE Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
ortho,para-dinitrophenyltropane[13] NO2 NO2 - - - - -

(3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes[edit]

Para-meta(3′)-meta(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes[14]
Para-methoxy/(ethoxy)-meta-substituted phenyltropanes
Structure
 Short Name
(All compounds tested as HCl salts) 		R2
3′-(meta) 		R3
5′-(di-meta) 		OR1
4′-(para) 		DAT
IC50
[3H](compound #)12 		5-HTT
Ki
[3H]Paroxetine 		NET
Ki
[3H]Nisoxetine 		Selectivity
NET/DAT
Ratio
Ki/IC50 		Selectivity
NET/5-HTT
Ratio
Ki/Ki
Cocaine - - - 89.1 95 1990 22 21
6
RTI-112		 - - - 0.82 ± 0.05 0.95 ± 0.04 21.8 ± 0.6 27 23
7a
11i		 H H CH3 6.5 ± 1.3 4.3 ± 0.5 1110 ± 64 171 258
7b H H C2H5 92 ± 8 1.7 ± 0.4 1690 ± 50 18 994
7c F H CH3 16 ± 1 4.8 ± 0.5 270 ± 50 17 56
7d Br H CH3 47 ± 15 3.1 ± 0.1 160 ± 20 3 52
7f Br Br CH3 92 ± 22 2.9 ± 0.1 4100 ± 400ɑ 45 1413
7e I H CH3 170 ± 60 3.5 ± 0.4 180 ± 20 1 51
7g I I CH3 1300 ± 200 7.5 ± 0.8 180 ± 20 4 667

ɑN=2

(2′,4′,5′-Trisubstituted phenyl)-tropanes[edit]

Ortho-para(4′)-meta(5′)-trisubstituted 2β-carbomethoxy-(2′,4′,5′-substituted phenyl)tropanes[3]
Structure Short Name R1
2′-(ortho) 		R2
4′-(para) 		R3
5′-(meta) 		DAT 5-HTT NET Selectivity
NET/DAT
Ratio 		Selectivity
NET/5-HTT
Ratio
para-ethyl-ortho, meta-diiodophenyltropane[3] iodo ethyl iodo - - - - -

2-Carbmethoxy modified (replaced/substituted)[edit]

General 2-carbmethoxy modifications[edit]

2β-substitutions of p-methoxy-phenyltropanes[edit]

Para-OCH3-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues[15]
Structure
 Short Name
(All compounds tested as HCl salts) 		CO2R (2β-substituted)
(compound 9 is 2β=R) 		DAT
IC50
[3H](compound #)12 		5-HTT
Ki
[3H]Paroxetine 		NET
Ki
[3H]Nisoxetine 		Selectivity
NET/DAT
Ratio
Ki/IC50 		Selectivity
NET/5-HTT
Ratio
Ki/Ki
7a
11i		 CH3 6.5 ± 1.3 4.3 ± 0.5 1110 ± 64 171 258
8a (CH3)2CH 14 ± 3 135 ± 35 2010 ± 200 144 15
8b cyclopropane 6.0 ± 2 29 ± 3 1230 ± 140 205 42
8c cyclobutane 13 ± 3 100 ± 8 >3000 231 30
8d O2N...1,4-xylene...(CH2)2 42 ± 8 2.9 ± 0.2 330 ± 20 8 114
8e H2N...1,4-xylene...(CH2)2 7.0 ± 2 8.3 ± 0.4 2200 ± 300ɑ 314 265
8f CH3CONH...1,4-xylene...(CH2)2 6.0 ± 1 5.5 ± 0.5 1460 ± 30 243 265
8g H2N...2-bromo-1,4-dimethylbenzene...(CH2)2 3.3 ± 1.4 4.1 ± 0.6 1850 ± 90 561 451
8h H2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)2 15 ± 6 2.0 ± 0.4 2710 ± 250ɑ 181 1360
8i H2N...2-iodo-1,4-dimethylbenzene...(CH2)2 2.5 ± 0.7 3.5 ± 1 2040 ± 300ɑ 816 583
8j H2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2 102 ± 15 1.0 ± 0.1 2600 ± 200ɑ 25 2600
9 3-(4-methylphenyl)-1,2-oxazole 18 ± 6 860 ± 170 >3000 167 3

ɑN=2

2β-carboxy side-chained (p-chloro/iodo/methyl) phenyltropanes[edit]

Multi-substituted structures of 2β-ester-3β-phenyltropanes[1]
Compound
 Short Name
(S. Singh) 		R X IC50 (nM)
DAT
[3H]WIN 35428 		IC50 (nM)
5-HTT
[3H]paroxetine 		IC50 (nM)
NET
[3H]nisoxetine 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
23a CH(CH3)2 H 85.1 ± 2.5 23121 ± 3976 32047 ± 1491 272 376
23b C6H5 H 76.7 ± 3.6 106149 ± 7256 19262 ± 593 1384 251
24a CH(CH3)2 Cl 1.4 ± 0.13
6.04 ± 0.31ɑ		 1400 ± 7
128 ± 15b		 778 ± 21
250 ± 0.9c		 1000
21.2d		 556
41.4e
24b cyclopropyl Cl 0.96 ± 0.10 168 ± 1.8 235 ± 8.39 175 245
24c C6H5 Cl 1.99 ± 0.05
5.25 ± 0.76ɑ		 2340 ± 27
390 ± 34b		 2960 ± 220
242 ± 30c		 1176
74.3d		 1.3
41.6e
24d C6H4-4-I Cl 32.6 ± 3.9 1227 ± 176 967.6 ± 26.3 37.6 29.7
24e C6H4-3-CH3 Cl 9.37 ± 0.52 2153 ± 143 2744 ± 140 230 293
24f C6H4-4-CH3 Cl 27.4 ± 1.5 1203 ± 42 1277 ± 118 43.9 46.6
24g C6H4-2-CH3 Cl 3.91 ± 0.23 3772 ± 384 4783 ± 387 965 1223
24h C6H4-4-Cl Cl 55 ± 2.3 16914 ± 1056 4883 ± 288 307 88.8
24i C6H4-4-OCH3 Cl 71 ± 5.6 19689 ± 1843 1522 ± 94 277 21.4
24j (CH2)2C6H4-4-NO2 Cl 2.71 ± 0.13 - - - -
24k (CH)2C6H4-4-NH2 Cl 2.16 ± 0.25 - - - -
24l (CH2)2C6H3-3-I-4-NH2 Cl 2.51 ± 0.25 - - - -
24m (CH2)2C6H3-3-I-4-N3 Cl 14.5 ± 0.94 - - - -
24n (CH2)2C6H4-4-N3 Cl 6.17 ± 0.57 - - - -
24o (CH2)2C6H4-4-NCS Cl 5.3 ± 0.6 - - - -
24p (CH2)2C6H4-4-NHCOCH2Br Cl 1.73 ± 0.06 - - - -
25a CH(CH3)2 I 0.43 ± 0.05
2.79 ± 0.13ɑ		 66.8 ± 6.53
12.5 ± 1.0b		 285 ± 7.6
41.2 ± 3.0c		 155
4.5d		 663
14.8e
25b cyclopropyl I 0.61 ± 0.08 15.5 ± 0.72 102 ± 11 25.4 167
25c C6H5 I 1.51 ± 0.34
6.85 ± 0.93ɑ		 184 ± 22
51.6 ± 6.2b		 3791 ± 149
32.7 ± 4.4c		 122
7.5d		 2510
4.8e
26a CH(CH3)2 CH3 6.45 ± 0.85
15.3 ± 2.08ɑ		 6090 ± 488
917 ± 54b		 1926 ± 38
73.4 ± 11.6c		 944
59.9d		 299
4.8e
26b CH(C2H5)2 CH3 19.1 ± 1 4499 ± 557 3444 ± 44 235 180
26c cyclopropyl CH3 17.8 ± 0.76 485 ± 21 2628 ± 252 27.2 148
26d cyclobutyl CH3 3.74 ± 0.52 2019 ± 133 4738 ± 322 540 1267
26e cyclopentyl CH3 1.68 ± 0.14 1066 ± 109 644 ± 28 634 383
26f C6H5 CH3 3.27 ± 0.06
9.13 ± 0.79ɑ		 24500 ± 1526
1537 ± 101b		 5830 ± 370
277 ± 23c		 7492
168d		 1783
30.3e
26g C6H4-3-CH3 CH3 8.19 ± 0.90 5237 ± 453 2136 ± 208 639 261
26h C6H4-4-CH3 CH3 81.2 ± 16 15954 ± 614 4096 ± 121 196 50.4
26i C6H4-2-CH3 CH3 23.2 ± 0.97 11040 ± 504 25695 ± 1394 476 1107
26j C6H4-4-Cl CH3 117 ± 7.9 42761 ± 2399 9519 ± 864 365 81.3
26k C6H4-4-OCH3 CH3 95.6 ± 8.8 82316 ± 7852 3151 ± 282 861 33.0
  • ɑKi value for displacement of [3H]DA uptake.
  • bKi value for displacement of [3H]5-HT uptake.
  • cKi value for displacement of [3H]NE uptake.
  • d[3H]5-HT uptake to [3H]DA uptake ratio.
  • e[3H]NE uptake to [3H]DA uptake ratio.

Carboxyaryl[edit]

Compound X 2 Position config 8 DA 5-HT NE
RTI-122 I -CO2Ph β,β NMe 1.50 184 3,791
RTI-113 Cl -CO2Ph β,β NMe 1.98 2,336 2,955
RTI-277 NO2 -CO2Ph β,β NMe 5.94 2,910 5,695
RTI-120 [recheck] Me -CO2Ph β,β NMe 3.26 24,471 5,833
RTI-116 Cl -CO2(p-C6H4I) β,β NMe 33 1,227 968
RTI-203 Cl CO2(m-C6H4Me) β,β NMe 9.37 2153 2744
RTI-204 Cl -CO2(o-C6H4Me) β,β NMe 3.91 3,772 4,783
RTI-205 Me -CO2(m-C6H4Me) β,β NMe 8.19 5,237 2,137
RTI-206 Cl -CO2(p-C6H4Me) β,β NMe 27.4 1,203 1,278

2-Phenyl-3-Phenyltropanes[edit]

2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake[1]
Compound Structure Short Name
(S. Singh) 		Stereochemistry X
(para) 		DAT
[3H]WIN 35428 IC50 (nM) 		DAT
[3H]Mazindol Ki (nM) 		5-HTT
[3H]Paroxetine IC50 (nM) 		[3H]DA uptake Ki (nM) [3H]5-HT uptake Ki (nM) Selectivity
[3H]5-HT/[3H]DA
Cocaine (2β,3β) (H) 89 ± 4.8 281 1050 ± 89 423 155 0.4
67a 2β,3β H 12.6 ± 1.8 14.9 21000 ± 3320 28.9 1100 38.1
67b 2β,3α H - 13.8 - 11.7 753 64.3
67c 2α,3α H 690 ± 37 - 41300 ± 5300 - - -
68 2β,3α F - 6.00 - 4.58 122 26.6
69a 2β,3β CH3 1.96 ± 0.08 2.58 11000 ± 83 2.87 73.8 25.7
69b 2β,3α CH3 - 2.87 - 4.16 287 69.0
69c 2α,3α CH3 429 ± 59 - 15800 ± 3740 - - -

Carboxyalkyl[edit]

Code X 2 Position config 8 DA 5-HT NE
RTI-77 Cl CH2C2(3-iodo-p-anilino) β,β NMe 2.51 — 2247
RTI-121 IPCIT I -CO2Pri β,β NMe 0.43 66.8 285
RTI-153 I -CO2Pri β,β NH 1.06 3.59 132
RTI-191 I -CO2Prcyc β,β NMe 0.61 15.5 102
RTI-114 Cl -CO2Pri β,β NMe 1.40 1,404 778
RTI-278 NO2 -CO2Pri β,β NMe 8.14 2,147 4,095
RTI-190 Cl -CO2Prcyc β,β NMe 0.96 168 235
RTI-193 Me -CO2Prcyc β,β NMe 1.68 1,066 644
RTI-117 Me -CO2Pri β,β NMe 6.45 6,090 1,926
RTI-150 Me -CO2Bucyc β,β NMe 3.74 2,020 4,738
RTI-127 Me -CO2C(H)Et2 β,β NMe 19 4500 3444
RTI-338 ethyl -CO2C2Ph β,β NMe 1104 7.41 3366

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.

2-Alkyl Esters & Ethers[edit]

Esters (2-Alkyl)[edit]
2β-Alkyl Ester Phenyltropanes[1]
Structure Short Name
(S. Singh) 		2β=R Ki (nM)
DAT
[3H]WIN 35428 		IC50 (nM)
[3H]DA uptake 		Selectivity
uptake/binding
59a CH=CHCO2CH3 22 ± 2 123 ± 65 5.6
59b CH2CH2CO2CH3 23 ± 2 166 ± 68 7.2
59c (CH2)2CH=CHCO2CH3 20 ± 2 203 ± 77 10.1
59d (CH22)4CO2CH3 30 ± 2 130 ± 7 4.3
59e CH=CHCH2OH 26 ± 3 159 ± 43 6.1
59f CH2CH2CH2OH 11 ± 1 64 ± 32 5.8
59g CH2CH2COC6H5 28 ± 2 47 ± 15 1.7
Ethers (2-Alkyl)[edit]

See the N-desmethyl Paroxetine homologues

2-Alkyl Ether Phenyltropanes[1]
Molecular Structure Short Name
(S. Singh) 		Stereochemistry DAT
[3H]WIN 35428 IC50 (nM) 		5-HTT
[3H]Paroxetine IC50 (nM) 		NET
[3H]Nisoxetine IC50 (nM) 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
Paroxetine 623 ± 25 0.28 ± 0.02 535 ± 15 0.0004 0.8
R-60a 2β,3β 308 ± 20 294 ± 18 5300 ± 450 0.9 17.2
R-60b 2α,3β 172 ± 8.8 52.9 ± 3.6 26600 ± 1200 0.3 155
R-60c 2β,3α 3.01 ± 0.2 42.2 ± 16 123 ± 9.5 14.1 40.9
S-60d 2β,3β 1050 ± 45 88.1 ± 2.8 27600 ± 1100 0.08 26.3
S-60e 2α,3β 1500 ± 74 447 ± 47 2916 ± 1950 0.3 1.9
S-60f 2β,3α 298 ± 17 178 ± 13 12400 ± 720 0.6 41.6

Carboxamides[edit]

U.S. patent 5,736,123

Structure Code
(S. Singh #)		 X 2 Position config 8 DA
[3H]WIN 35428 (IC50 nM)		 NE
[3H]nisoxetine		 5-HT
[3H]paroxetine (IC50 nM)		 Selectivity
5-HTT/DAT		 Selectivity
NET/DAT
RTI-106
27b		 Cl CON(H)Me β,β NMe 12.4 ± 1.17 1584 ± 62 1313 ± 46 106 128
RTI-118
27a		 Cl CONH2 β,β NMe 11.5 ± 1.6 4270 ± 359 1621 ± 110 141 371
RTI-222
29d		 Me morpholinyl β,β NMe 11.7 ± 0.87 23601 ± 1156 >100K >8547 2017
RTI-129
27e		 Cl CONMe2 β,β NMe 1.38 ± 0.1 942 ± 48 1079 ± 102 792 683
RTI-146
27d		 Cl CONHCH2OH β,β NMe 2.05 ± 0.23 144 ± 3 97.8 ± 10 47.7 70.2
RTI-147
27i		 Cl CON(CH2)4 β,β NMe 1.38 ± 0.03 3,950 ± 72 12400 ± 1207 8985 2862
RTI-156 Cl CON(CH2)5 β,β NMe 6.61 5832 3468
RTI-170 Cl CON(H)CH2C≡CH β,β NMe 16.5 1839 4827
RTI-172 Cl CON(H)NH2 β,β NMe 44.1 3914 3815
RTI-174 Cl CONHCOMe β,β NMe 158 >43K >125K
RTI-182 Cl CONHCH2COPh β,β NMe 7.79 1722 827
RTI-183✲
27 g		 Cl CON(OMe)Me β,β NMe 0.85 ± 0.06 549 ± 18.5 724 ± 94 852 646
RTI-186
29c		 Me CON(OMe)Me β,β NMe 2.55 ± 0.43 422 ± 26 3402 ± 353 1334 165
RTI-198
27h		 Cl CON(CH2)3 β,β NMe 6.57 ± 0.67 990 ± 4.8 814 ± 57 124 151
RTI-196
27c		 Cl CONHOMe β,β NMe 10.7 ± 1.25 9907 ± 632 43700 ± 1960 4084 926
RTI-201 Cl CONHNHCOPh β,β NMe 91.8 >20K >48K
RTI-208
27j		 Cl CONO(CH2)3 β,β NMe 1.47 ± 0.13 1083 ± 76 2470 ± 56 1680 737
RTI-214
27l		 Cl CON(-CH2CH2-)2O β,β NMe 2.90 ± 0.3 8545 ± 206 88769 ± 1855 30610 2946
RTI-215
27f		 Cl CONEt2 β,β NMe 5.48 ± 0.19 5532 ± 299 9433 ± 770 1721 1009
RTI-217 Cl CONH(m-C6H4OH) β,β NMe 4.78 >30K >16K
RTI-218✲ Cl CON(Me)OMe β,β NMe 1.19 520 1911
RTI-226
27 m		 Cl CONMePh β,β NMe 45.5 ± 3 2202 ± 495 23610 ± 2128 519 48.4
RTI-227 I CONO(CH2)3 β,β NMe 0.75 446 230
RTI-229[16]
28a		 I CON(CH2)4 β,β NMe 0.37 ± 0.04 991 ± 21 1728 ± 39 4670 2678
27k 6.95 ± 1.21 1752 ± 202 3470 ± 226 499 252
28b 1.08 ± 0.15 103 ± 6.2 73.9 ± 8.1 68.4 95.4
28c 0.75 ± 0.02 357 ± 42 130 ± 15.8 173 476
29a 41.8 ± 2.45 4398 ± 271 6371 ± 374 152 105
29b 24.7 ± 1.93 6222 ± 729 33928 ± 2192 1374 252

✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.

2β-Carboxamide-3β-Phenyltropanes[1]
Compound Short Name
(S. Singh) 		R X IC50 (nM)
DAT
[3H]WIN 35428 		IC50 (nM)
5-HTT
[3H]Paroxetine 		IC50 (nM)
NET
[3H]Nisoxetine 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
29a NH2 CH3 41.8 ± 2.45 6371 ± 374 4398 ± 271 152 105
29b N(CH2CH3)2 CH3 24.7 ± 1.93 33928 ± 2192 6222 ± 729 1374 252
29c
RTI-186		 N(OCH3)CH3 CH3 2.55 ± 0.43 3402 ± 353 422 ± 26 1334 165
29d
RTI-222		 4-morpholine CH3 11.7 ± 0.87 >100000 23601 ± 1156 >8547 2017

Carboxamide linked phenyltropanes dimers[edit]


Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo.[3]

Heterocycles[edit]

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize[17] to the energetically more favorable trans configuration. This can happen to cocaine also.

Atomic positions A—C
(compound model 34)

Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔVmin(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔVmin(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔVmin is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.[g]

3-Substituted-isoxazol-5-yl[edit]

N-methylphenyltropanes with 1R β,β stereochemistry.
Code
(S.S. #) 		X R DA NE 5HT
RTI-165 Cl 3-methylisoxazol-5-yl 0.59 181 572
RTI-171 Me 3-methylisoxazol-5-yl 0.93 254 3818
RTI-180 I 3-methylisoxazol-5-yl 0.73 67.9 36.4
RTI-177 β-CPPIT
32g		 Cl 3-phenylisoxazol-5-yl 1.28 ± 0.18 504 ± 29 2420 ± 136
RTI-176 Me 3-phenylisoxazol-5-yl 1.58 398 5110
RTI-181 I 3-phenylisoxazol-5-yl 2.57 868 100
RTI-184 H methyl 43.3 — 6208
RTI-185 H Ph 285 — >12K
RTI-334 Cl 3-ethylisoxazol-5-yl 0.50 120 3086
RTI-335 Cl isopropyl 1.19 954 2318
RTI-336 Cl 3-(4-methylphenyl)isoxazol-5-yl 4.09 1714 5741
RTI-337 Cl 3-t-butyl-isoxazol-5-yl 7.31 6321 37K
RTI-345 Cl p-chlorophenyl 6.42 5290 >76K
RTI-346 Cl p-anisyl 1.57 762 5880
RTI-347 Cl p-fluorophenyl 1.86 918 7257
RTI-354 Me 3-ethylisoxazol-5-yl 1.62 299 6400
RTI-366 Me R = isopropyl 4.5 2523 (1550) 42,900 (3900)
RTI-371 Me p-chlorophenyl 8.74 >100K (60,200) >100K (9090)
RTI-386 Me p-anisyl 3.93 756 (450) 4027 (380)
RTI-387 Me p-fluorophenyl 6.45 917 (546) >100K (9400)

3-Substituted-1,2,4-oxadiazole[edit]

Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.
Structure Code
(Singh's #) 		X R DAT (IC50 nM)
displacement of [H3]WIN 35428 		NET (IC50 nM)
[H3]nisoxetine 		5-HTT (IC50 nM)
[H3]paroxetine 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
ααRTI-87 H 3-methyl-1,2,4-oxadiazole 204 36K 30K
βαRTI-119 H 3-methyl-1,2,4-oxadiazole 167 7K 41K
αβRTI-124 H 3-methyl-1,2,4-oxadiazole 1028 71K 33K
RTI-125
(32a)		 Cl 3-methyl-1,2,4-oxadiazole 4.05 ± 0.57 363 ± 36 2584 ± 800 637 89.6
ββRTI-126[18]
(31)		 H 3-methyl-1,2,4-oxadiazole 100 ± 6 7876 ± 551 3824 ± 420 38.3 788
RTI-130
(32c)		 Cl 3-phenyl-1,2,4-oxadiazole 1.62 ± 0.02 245 ± 13 195 ± 5 120 151
RTI-141
(32d)		 Cl 3-(p-anisyl)-1,2,4-oxadiazole 1.81 ± 0.19 835 ± 8 337 ± 40 186 461
RTI-143
(32e)		 Cl 3-(p-chlorophenyl)-1,2,4-oxadiazole 4.06 ± 0.22 40270 ± 180
(4069)		 404 ± 56 99.5 9919
RTI-144
(32f)		 Cl 3-(p-bromophenyl)-1,2,4-oxadiazole 3.44 ± 0.36 1825 ± 170 106 ± 10 30.8 532
βRTI-151
(33)		 Me 3-phenyl-1,2,4-oxadiazole 2.33 ± 0.26 60 ± 2 1074 ± 130 459 25.7
αRTI-152 Me 3-phenyl-1,2,4-oxadiazole 494 — 1995
RTI-154
(32b)		 Cl 3-isopropyl-1,2,4-oxadiazole 6.00 ± 0.55 135 ± 13 3460 ± 250 577 22.5
RTI-155 Cl 3-cyclopropyl-1,2,4-oxadiazole 3.41 177 4362
RTI-4229-470 structure. Highly excited 94 pM DAT signal.[19]

↑ above: 2D skeletal depiction.

↓ below: 3D tube model.
N-methylphenyltropanes with 1R β,β stereochemistry.
Structure Code X 2 Group DAT (IC50 nM)
displacement of [H3]WIN 35428 		NET (IC50 nM)

displacement of [H3]nisoxetine 		5-HTT (IC50 nM)

displacement of [H3]paroxetine 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
RTI-157 Me tetrazole 1557 >37K >43K
RTI-163 Cl tetrazole 911 — 5456
RTI-178 Me 5-phenyl-oxazol-2-yl 35.4 677 1699
RTI-188 Cl 5-phenyl-1,3,4-oxadiazol-2-yl 12.6 930 3304
RTI-189
(32i)		 Cl 5-phenyl-oxazol-2-yl 19.7 ± 1.98 496 ± 42 1120 ± 107 56.8 25.5
RTI-194 Me 5-methyl-1,3,4-oxadiazol-2-yl 4.45 253 4885
RTI-195 Me 5-phenyl-1,3,4-oxadiazol-2-yl 47.5 1310 >22,000
RTI-199 Me 5-phenyl-1,3,4-thiadiazol-2-yl 35.9 >24,000 >51,000
RTI-200 Cl 5-phenyl-1,3,4-thiadiazol-2-yl 15.3 4142 >18,000
RTI-202 Cl benzothiazol-2-yl 1.37 403 1119
RTI-219 Cl 5-phenylthiazol-2-yl 5.71 8516 10,342
RTI-262 Cl 188.2 ± 5.01 595.25 ± 5738 5207 ± 488 316 28
RTI-370 Me 3-(p-cresyl)isoxazol-5-yl 8.74 6980 >100K
RTI-371 Cl 3-(p-chlorophenyl)isoxazol-5-yl 13 >100K >100K
RTI-436 Me -CH=CHPh[20] 3.09 1960 (1181) 335 (31)
RTI-470 Cl o-Cl-benzothiazol-2-yl 0.094 1590 (994) 1080 (98)
RTI-451 Me benzothiazol-2-yl 1.53 476 (287) 7120 (647)
32g 1.28 ± 0.18 504 ± 29 2420 ± 136 1891 394
32h 12.6 ± 10.3 929 ± 88 330 ± 196 262 73.7
Above is taken from: RTI, Kuhar, et al. U.S. patent 5,935,953 (1999).

N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).

Acyl (C2-propanoyl)[edit]

Indolyl[21]
cf. the Tamagnan series of phenyltropanes for examples with a methylene unit spacer breaking up the indole.
#
(#)		 X Y 2 Position config 8 DA 5-HT NE
WF-23
(39n)		 β-naphthyl C(O)Et β,β NMe 0.115 0.394 No data
WF-31 PIT -Pri H C.O.Et β,β NMe 615 54.5 No data
WF-11✲ PTT
(39e)		 Me H -C.O.Et β,β NMe 8.2 131 No data
WF-25
(39a)		 H H -C.O.Et β,β NMe 48.3 1005 No data
WF-33 6-MeoBN C(O)Et α,β NMe 0.13 2.24 No data
✲Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)
2β-acyl-3β-phenyltropane structures[h]
Structure S. Singh's
alphanumeric
assignation
(name) 		R1 R2 DAT

[125I]RTI-55 IC50 (nM)

5-HTT

[3H]Paroxetine Ki (nM)

Selectivity

5-HTT/DAT

cocaine 173 ± 19 — —
Troparil
11a
(WIN 35065-2)		 98.8 ± 12.2 — —
WF-25
39a		 C2H5 C6H5 48.3 ± 2.8 1005 ± 112 20.8
39b CH3 C6H5 114 ± 22 1364 ± 616 12.0
39c C2H5 C6H4-4-F 15.3 ± 2.8 630 ± 67 41.2
39d CH3 C6H4-4-F 70.8 ± 13 857 ± 187 12.1
WF-11
39e		 C2H5 C6H4-4-CH3 8.2 ± 1.6 131 ± 1 16.0
(+)-39e C2H5 C6H4-4-CH3 4.21 ± 0.05 74 ± 12 17.6
(-)-39e C2H5 C6H4-4-CH3 1337 ± 122 >10000 —
39f CH3 C6H4-4-CH3 9.8 ± 0.5 122 ± 22 12.4
39g CH3 C6H4-4-C2H5 152 ± 24 78.2 ± 22 0.5
39h C2H5 C6H4-4-CH(CH3)2 436 ± 41 35.8 ± 4.4 0.08
39i C2H5 C6H4-4-C(CH3)3 2120 ± 630 1771 ± 474 0.8
39j C2H5 C6H4-4-C6H5 2.29 ± 1.08 4.31 ± 0.01 1.9
39k C2H5 C6H4-2-CH3 1287 ± 322 710000 >7.8
39l C2H5 1-naphthyl 5.43 ± 1.27 20.9 ± 2.9 3.8
39m CH3 1-naphthyl 10.1 ± 2.2 25.6 ± 5.1 2.5
WF-23
39n		 C2H5 2-naphthyl 0.115 ± 0.021 0.394 ± 0.074 3.5
39o CH3 2-naphthyl 0.28 ± 0.11 1.06 ± 0.36 3.8
39p C2H5 C6H4-4-CH(C2H5)2 270 ± 38 540 ± 51 2.0
39q C2H5 C6H4-4-C6H11 320 ± 55 97 ± 12 0.30
39r C2H5 C6H4-4-CH=CH2 0.90 ± 0.34 3.2 ± 1.3 3.5
39s C2H5 C6H4-4-C(=CH2)CH3 7.2 ± 2.1 0.82 ± 0.38 0.1

2β-Acyl-3β-naphthyl substituted[edit]

2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes[22]
Structure Short Assignation
(Numeric code, Davies UB)
S. Singh 		R DAT
[125H]RTI-55ɑ
IC50 nM 		SERT
[3H]paroxetineb
Ki nM 		NET
[3H]nisoxetinec
Ki nM 		potency ratio
SERT/DAT 		potency ratio
SERT/NET
WF-11
(6)		 4′-Me 8.2 ± 1.6 131 ± 10 65 ± 9.2 0.06 0.5
WF-31
(7)		 4′-iPr 436 ± 41 36 ± 4 >10,000 12 >250
WF-23
(8)		 2-naphthalene 0.12 ± 0.02 0.39 ± 0.07 2.9 ± 0.5 0.3 7
2β-acyl-3β-1-naphthalene
(9a)		 4′-H 5.3 ± 1.3 21 ± 2.9 49 ± 10 0.3 18
(9b) 4′-Me 25.1 ± 0.5 8.99 ± 1.70 163 ± 36 3 18
(9c) 4′-Et 75.1 ± 11.9 175 ± 25 4769 ± 688 0.7 27
(9d) 4′-iPr 225 ± 36 136 ± 64 >10,000 2 >73.5
(10a) 6′-Et 0.15 ± 0.04 0.38 ± 0.19 27.7 ± 9.6 0.4 74
(10b) 6′-iPr 0.39 ± 0.04 1.97 ± 0.33 no data 0.2 —
(10ce) 6′- OMe 0.13 ± 0.04 2.24 ± 0.34 no data 0.05 —
(10d) 5′-Et, 6′-OMe 30.8 ± 6.6 7.55 ± 1.57 3362 ± 148 4.1 445
(10e) 5′-C(Me)=CH2, 6′-OMe 45.0 ± 3.7 88.0 ± 13.3 2334 ± 378 0.5 26.5
(10f) 6′-I 0.35 ± 0.07 0.37 ± 0.02 no data 1.0 —
(10g) 7′-I 0.45 ± 0.05 0.47 ± 0.02 no data 0.5d —
(10h) 5′-NO2, 6′-OMe 148 ± 50 15 ± 1.6 no data 10 —
(10i) 5′-I, 6′-OMe 1.31 ± 0.33 2.27 ± 0.31 781 ± 181 0.6 344
(10j) 5′-COMe, 6′-OMe 12.6 ± 3.8 15.8 ± 1.65 498 ± 24 0.8 32
(11a) 2β-COCH3, 1-naphthyl 10 ± 2.2 26 ± 5.1 165 ± 40 0.4 6.3
(11b) 2α-COCH3, 1-naphthyl 97 ± 21 217 ± 55 no data 0.45 —
(11c) 2α-COCH2CH3, 2-naphthyl 2.51 ± 0.82 16.4 ± 2.0 68.0 ± 10.8 0.15 4.1
(11d) 2β-COCH3, 2-naphthyl 1.27 ± 0.15 1.06 ± 0.36 4.9 ± 1.2 1.2 4.6
(11e) 2β-COCH(CH3)2, 2-naphthyl 0.25 ± 0.08 2.08 ± 0.80 37.6 ± 10.5 0.12 18.1
(11f)
79a		 2β-COCH2CH3, 2-naphthyl, N8-demethyl 0.03 ± 0.01 0.23 ± 0.07 2.05 ± 0.9 0.13 8.9
  • ɑ nonspecific binding was determined in the presence of 1.0 μM WF-23
    (source equates WF-23 as analogue 3a, but table gives # as analogue 8)
  • b nonspecific binding was determined in the presence of 10.0 μM fluoxetine
  • c nonspecific binding was determined in the presence of 1.0 μM desipramine
  • d ratio shown as halved; a possible copy-error due to closeness to 1:1 of other indicated values
  • e sources differ on whether C2 position acyl is alpha or beta configured

Ester reduction[edit]

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

Code X 2 Position config 8 DA 5-HT NE
RTI-100 F -CH2OH β,β NMe 47 4741 no data
RTI-101 I -CH2OH β,β NMe 2.2 26 no data
RTI-99 Br -CH2OH β,β NMe 1.49 51 no data
RTI-93 Cl -CH2OH β,β NMe 1.53 204 43.8
RTI-105 Cl -CH2OAc β,β NMe 1.60 143 127
RTI-123 Cl -CH2OBz β,β NMe 1.78 3.53 393
RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2.93 1.48

2-Alkane/Alkene[edit]

2-Alkane/Alkene-3-Phenyltropanes
Structure Singh's # R X DAT
mazindol displacement 		DA uptake 5-HT Uptake Selectivity
DA uptake/DAT binding
11a
WIN 35062-2		 89.4 53.7 186 0.6
11c 0.83 ± 00.7 28.5 ± 0.9 — 34.3
11f 5.76 6.92 23.2 1.2
41a (CH2)2CH3 H 12.2 6.89 86.8 0.6
41b (CH2)3C6H5 H 16 ± 2a 43 ± 13b — 2.7
42 (CH2)2CH3 F 5.28 1.99 21.7 0.4
43a CH=CH2 Cl 0.59 ± 0.15 2.47 ± 0.5 — 4.2
43b E-CH=CHCl Cl 0.42 ± 0.04 1.13 ± 0.27 — 2.7
43c Z-CH=CHCl Cl 0.22 ± 0.02 0.88 ± 0.05 — 4.0
43d E-CH=CHC6H5 Cl 0.31 ± 0.04 0.66 ± 0.01 — 2.1
43e Z-CH=CHC6H5 Cl 0.14 ± 0.07 0.31 ± 0.09 — 2.2
43f CH2CH3 Cl 2.17 ± 0.20 2.35 ± 0.52 — 1.1
43 g (CH2)2CH3 Cl 0.94 ± 0.08 1.08 ± 0.05 — 1.1
43h (CH2)3CH3 Cl 1.21 ± 0.18 0.84 ± 0.05 — 0.7
43i (CH2)5CH3 Cl 156 ± 15 271 ± 3 — 1.7
43j (CH2)2C6H5 Cl 1.43 ± 0.03 1.54 ± 0.08 — 1.0
44a (CH2)2CH3 CH3 1.57 1.10 10.3 0.7
44b (CH2)3CH3 CH3 1.82 1.31 15.1 0.7
45 (CH2)2CH3 H 74.9 30.2 389 0.4
46 (CH2)2CH3 F 21.1 12.1 99.6 0.6
47a (CH2)2CH3 CH3 8.91 11.8 50.1 1.3
47b (CH2)3CH3 CH3 11.4 10.1 51.0 0.9

aKi value for displacement of WIN 35428.
bIC50 value.

Compound 48
para-hydro
para-chloro

Irreversible covalent (cf. ionic) C2 ligands[edit]


Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics. 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID 18492949. S2CID 5996473.)[23] RTI-76:[24] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

C2 Acyl, N8 phenylisothiocyanate[edit]


HD-205 (Murthy et al., 2007)[25]

Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

Benztropine based (C2-position hetero-substituted) phenyltropanes[edit]


2-(Diarylmethoxymethyl)-3β-aryltropanes & 2β-[3-(Diarylmethoxy)propyl]-3β-aryltropanes.[26][27]
Structure Compound R X Y [3H]WIN 35,428
@ DAT
Ki (nM) 		[3H]Citalopram
@ SERT
Ki (nM) 		[3H]Nisoxetine
@ NET
Ki (nM) 		[3H]Pirenzepine
@ M1
Ki (nM)
9a CH3 H H 34 ± 2 121 ± 19 684 ± 100 10,600 ± 1,100
9b F H H 49 ± 12 — — —
9c Cl H H 52 ± 2.1 147 ± 8 1,190 ± 72 11,000 ± 1,290
9d CH3 Cl H 80 ± 9 443 ± 60 4,400 ± 238 31,600 ± 4,300
9e F Cl H 112 ± 11 — — —
9f Cl Cl H 76 ± 7 462 ± 36 2,056 ± 236 39,900 ± 5,050
9g CH3 F F 62 ± 7 233 ± 24 1,830 ± 177 15,500 ± 1,400
9h F F F 63 ± 13 — — —
9i Cl F F 99 ± 18 245 ± 16 2,890 ± 222 16,300 ± 1,300
10a CH3 H H 455 ± 36 530 ± 72 2,609 ± 195 12,600 ± 1,790
10c Cl H H 478 ± 72 408 ± 16 3,998 ± 256 11,500 ± 1,720
10d CH3 Cl H 937 ± 84 1,001 ± 109 22,500 ± 2,821 18,200 ± 2,600
10f Cl Cl H 553 ± 106 1,293 ± 40 5,600 ± 183 9,600 ± 600
10g CH3 F F 690 ± 76 786 ± 67 16,000 ± 637 9,700 ± 900
10i Cl F F 250 ± 40 724 ± 100 52,300 ± 13,600 9,930 ± 1,090
12a H H H 139 ± 15 61 ± 9 207 ± 30 7,970 ± 631
12b H Cl H 261 ± 19 45 ± 3 — 24,600 ± 2,930
12c H F F 60 ± 7 — — —

F&B series (Biotin side-chains etc.)[edit]

One patent claims a series of compounds with biotin-related sidechains are pesticides.[18]

Structure Code para-X C2-Tropane Position config DA NE 5-HT
— H F1 β,β — — —
RTI-224 Me F1c β,β 4.49 — 155.6
RTI-233 Me F2 β,β 4.38 516 73.6
RTI-235 Me F3d β,β 1.75 402 72.4
— — F3 β,β — — —
RTI-236 Me B1d β,β 1.63 86.8 138
RTI-237 Me B2d β,β 7.27 258 363
RTI-244 Me B3d β,β 15.6 1809 33.7
RTI-245 Cl F4c β,β 77.3 — —
RTI-246 Me F4c β,β 50.3 3000 —
— — F5 β,β — — —
RTI-248 Cl F6c β,β 9.73 4674 6.96
RTI-249 Cl F1c β,β 8.32 5023 81.6
RTI-266 Me F2 β,β 4.80 836 842
RTI-267 Me F7 wrong β,β 2.52 324 455
RTI-268 Me F7 right β,β 3.89 1014 382
RTI-269 Me F8 β,β 5.55 788 986

Miscellany (i.e. Misc./Miscellaneous) C2-substituents[edit]

Structure Code X 2 Position config 8 DA 5-HT NE
RTI-102 I CO2H β,β NMe 474 1928 43,400
RTI-103 Br CO2H β,β NMe 278 3070 17,400
RTI-104 F CO2H β,β NMe 2744 >100K >100K
RTI-108 Cl -CH2Cl β,β NMe 2.64 98 129.8
RTI-241 Me -CH2CO2Me β,β NMe 1.02 619 124
RTI-139 Cl -CH3 β,β NMe 1.67 85 57
RTI-161 Cl -C≡N β,β NMe 13.1 1887 2516
RTI-230 Cl H3C–C=CH2 β,β NMe 1.28 57 141
RTI-240 Cl -CHMe2 β,β NMe 1.38 38.4 84.5
RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2,932 1,478
RTI-158 Me -C≡N β,β NMe 57 5095 1624
RTI-131 Me -CH2NH2 β,β NMe 10.5 855 120
RTI-164 Me -CH2NHMe β,β NMe 13.6 2246 280
RTI-132 Me -CH2NMe2 β,β NMe 3.48 206 137
RTI-239 Me -CHMe2 β,β NMe 0.61 114 35.6
RTI-338 Et -CO2CH2Ph β,β NMe 1104 7.41 3366
RTI-348 H -Ph β,β NMe 28.2 >34,000 2670

C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes)[edit]

Aryl-Tropenes[edit]

WO 2004113297, Peters, Dan; Olsen, Gunnar M. & Nielsen, Elsebet Oestergaard et al., "Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-12-29, assigned to NeuroSearch AS 

Test compound DA-uptake IC50(μM) NA-uptake IC50(μM) 5-HT-uptake IC50(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene 0.26 0.028 0.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene 0.058 0.013 0.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene 0.034 0.018 0.00023
US 0 
8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES
Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 0.079 0.026 0.0047

U.S. patent 2,001,047,028

Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 18 4.9 0.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 1.5 0.5 0.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 22.00 8.00 0.0036

Enantioselective nonstandard configurations (non-2β-,3β-)[edit]

β,α Stereochemistry[edit]

Structure Compound
(RTI #)
(S. Singh's #)		 X 2 Group config 8 DAT IC50 (nM)
[3H]WIN 35428		 5-HTT IC50 (nM)
[3H]paroxetine		 NET IC50 (nM)
[3H]nisoxetine		 selectivity
5-HTT/DAT		 selectivity
NET/DAT
RTI-140
20a		 H CO2Me β,α NMe 101 ± 16 5,701 ± 721 2,076 ± 285 56.4 20.6
RTI-352ɑ
20d		 I CO2Me β,α NMe 2.86 ± 0.16 64.9 ± 1.97 52.4 ± 4.9 22.8 18.4
RTI-549 Br CO2Me β,α NMe — — — — —
RTI-319b 3α-2-naphthyl CO2Me β,α NMe 1.1 ± 0.09 11.4 ± 1.3 70.2 ± 6.28 — —
RTI-286c
20b		 F CO2Me β,α NMe 21 ± 0.57 5062 ± 485 1231 ± 91 241 58.6
RTI-274d F CH2O(3′,4′-MD-phenyl) β,α NH 3.96 5.62 14.4 — —
RTI-287 Et CO2Me β,α NMe 327 1687 17,819 — —
20c Cl CO2Me β,α NMe 2.4 ± 0.2 998 ± 120 60.1 ± 2.4 416 25.0
20e Me CO2Me β,α NMe 10.2 ± 0.08 4250 ± 422 275 ± 24 417 27.0
Bn CO2Me β,α NMe — — — — —
ɑU.S. patent 6,358,492bU.S. patent 7,011,813cU.S. patent 7,011,813dU.S. patent 7,291,737

α,β Stereochemistry[edit]

CA 2112084 

Compound DA (μM) M.E.D. (mg/kg) Dose (mg/kg) Activity Activity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane 0.39 <1 50 0 0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane 0.1 1 25 0 0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane 0.016 0.25 50 + +++

di-chloro; para- & meta- in tandem (α,β configured phenyltropanes)[edit]

U.S. patent 2,001,047,028

Compound X 2 Group config 8 DA 5-HT NE
Brasofensine Cl2 methyl aldoxime α,β NMe — — —
Tesofensine Cl2 ethoxymethyl α,β NMe 65 11 1.7
NS-2359 (GSK-372,475) Cl2 Methoxymethyl α,β NH — — —

fumaric acid salts (of α,β configured phenyltropanes)[edit]

WO 2004072075, Peters, Dan; Nielsen, Elsebet Oestergaard & Olsen, Gunnar M. et al., "Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-08-26, assigned to NeuroSearch AS 

Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.062 0.035 0.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.062 0.15 0.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.10 0.048 0.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.088 0.051 0.013

Arene equivalent alterations[edit]

η6-3β-(transition metal complexed phenyl)tropanes[edit]

×–substitution image of both the chromium & ruthenium benzene pi-symmetry facilitating PTs.

21b can be prepared from ferrocenes and perrhenate by a double ligand transfer (DLT) reaction.[28]

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule.[1] (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.[29]).

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity Ki values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.

Tricarbonyl-3β-chromium containing phenyltropane, having roughly twice the strength Ki affinity as parent compound at same mean affect.

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.[1]

Diagram indicating the triflate, in bracket, superimposed as a direct connection between the η6 benzene containing its transition metal fixed upon the η5-penta-methyl (five-methyls) cyclopenta-dienyl (five sided ring) alongside the benzene in three dimension.
Displacement of Receptor-Bound [3H]WIN 35428 and Inhibition of [3H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes[1]
Structure Compound #
(S. Singh)
Systematic name 		Ki (nM)ɑ IC50 (nM) selectivity
binding/uptake
21ac 17 ± 15b
224 ± 83		 418 24.6
21bd 2280 ± 183 3890 1.7
Cocaine 32 ± 5
388 ±221		 405 12.6
Troparil (11a) 33 ± 17
314 ± 222		 373 11.3
  • ɑThe binding data fit a two-site model better than a one-site model
  • bThe Ki value for the one-site model was 124 ± 10 nM
  • cIUPAC: [η6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
  • dIUPAC: [η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

3-(2-thiophene) and 3-(2-furan)[edit]

U.S. patent 7,247,643
Code Compound DA (μM) NE (μM) 5-HT (μM)
1 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt 0.30 0.0019 0.00052
2 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.36 0.0036 0.00042
3 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.31 0.00090 0.00036
4 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.92 0.0030 0.00053
5 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.074 0.0018 0.00074
6 (2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.19 0.0016 0.00054

Thiophenyltropanes[edit]

Diaryl[edit]

Fluoxetine homologue,[30] also: Hanna et al. (2007)[31]
cf. the paroxetine homologue PTs
ZIENT:[32]

6/7-tropane position substituted[edit]

2β-carbomethoxy 6/7 substituted[edit]

6/7-Substituted 2-carbomethoxy-phenyltropanes[1]
Structure Compound #
(S. Singh) 		Substitution DAT (IC50 nM)
displacement of [H3]WIN 35428 		5-HTT (IC50 nM)
[H3]Citalopram 		Selectivity
5-HTT/DAT
Cocaine H 65 ± 12 - -
103a 3β,2β, 7-OMe
3′,4′-Cl2		 86 ± 4.7 884 ± 100 10.3
103b 3β,2β, 7-OH
3′,4′-Cl2		 1.42 ± 0.03 28.6 ± 7.8 20.1
103c 3α,2β, 7-OH
3′,4′-Cl2		 1.19 ± 0.16 1390 ± 56 1168
104a 3β,2β, 6-OH
4′-Me		 215ɑ - -
104b 3β,2α, 6-OH
4′-Me		 15310ɑ - -
104c 3α,2β, 6-OH
4′-Me		 930ɑ - -
104d 3α,2α, 6-OH
4′-Me		 7860ɑ - -
  • ɑIC50 value for displacement of [H3]mazindol. IC50 for cocaine 288 nM for displacement of [H3]mazindol

3-butyl 6/7 substituted[edit]

6/7-Substituted 3-butyl-phenyltropanes[1]
Structure Compound #
(S. Singh) 		Substituent Ki nM
displacement of [H3]mazindol binding 		Ki nM
[H3]DA uptake 		Selectivity
uptake/binding
Cocaine H 270 ± 0.03 400 ± 20 1.5
121a 7β-CN 2020 ± 10 710 ± 40 0.3
121b 6β-CN 3040 ± 480 6030 ± 880 2.0
121c 7β-SO2Ph 4010 ± 310 8280 ± 1340 2.1
121d 6β-SO2Ph 4450 ± 430 8270 ± 690 1.8
121e 7α-OH 830 ± 40 780 ± 60 0.9
121f H 100 ± 10 61 ± 10 0.6
121g 7β-CN 24000 ± 3420 32100 ± 8540 1.3
121h 6β-CN 11300 ± 1540 26600 ± 3330 2.3
121i 7β-SO2Ph 7690 ± 2770 7050 ± 450 0.9
121j 6β-SO2Ph 4190 ± 700 8590 ± 1360 2.0
121k 7α-SO2Ph 3420 ± 1100 - -
121l 7β-SO2Ph, 7α-F 840 ± 260 2520 ± 290 3.0
121m 7α-F 200 ± 10 680 ± 10 3.4
121n 7β-F 500 ± 10 550 ± 140 1.1

intermediate 6- & 7-position synthesis modified phenyltropanes[edit]

6/7-synthetic intermediates[1]
Structure Compound #
(S. Singh) 		Substituent W Substituent X Substituent Y Substituent Z
(±)-122a CN H H H
(±)-122b H H CH H
(±)-122c H CH H H
(±)-122d H H H CH
(±)-122e SO2Ph H H H
(±)-122f H H SO2Ph H
(±)-122g H SO2Ph H H
(±)-122h SO2Ph F H H
(±)-122i F SO2Ph H H
(±)-122j H H SO2Ph F

8-tropane (bridgehead) position modified[edit]

Nortropanes (N-demethylated)[edit]

NS2359 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.[33] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.[34]

Selected ββ Nortropanes
Code
(S.S. #) 		X
para
(unless position otherwise given inline) 		DA 5HT NE
RTI-142
75b		 F 4.39 68.6 18.8
RTI-98
75d
Norɑ-RTI-55		 I 0.69 0.36 11.0
RTI-110
75c		 Cl 0.62 4.13 5.45
RTI-173
75f		 Et 49.9 8.13 122
RTI-279
Norɑ-RTI-280		 para-Me
meta-I		 5.98 ± 0.48 1.06 ± 0.10 74.3 ± 3.8
RTI-305
Norɑ-RTI-360/11y		 Ethynyl 1.24 ± 0.11 1.59 ± 0.2 21.8 ± 1.0
RTI-307
Norɑ-RTI-281/11z		 Propynyl 6.11 ± 0.67 3.16 ± 0.33 115.6 ± 5.1
RTI-309
Norɑ-11t		 Vinyl 1.73 ± 0.05 2.25 ± 0.17 14.9 ± 1.18
RTI-330
Norɑ-11s		 Isopropyl 310.2 ± 21 15.1 ± 0.97 —
RTI-353 para-Et
meta-I		 330.54 ± 17.12 0.69 ± 0.07 148.4 ± 9.15

ɑThe N-demethylated variant of (i.e. compound code-name after dash)

N-demethylating various β,β p-HC-phenyltropanes
N-Me compound code#
→
N-demethylated derivative
compound code # 		para-X [3H]Paroxetine [3H]WIN 35,428 [3H]Nisoxetine
11 g→75f Ethyl 28.4 → 8.13 55 → 49.9 4,029 → 122
11t→75i Vinyl 9.5 → 2.25 1.24 → 1.73 78 → 14.9
11y→75n Ethynyl 4.4 → 1.59 1.2 → 1.24 83.2 → 21.8
11r→75 g 1-Propyl 70.4 → 26 68.5 → 212 3,920 → 532
11v→75k trans-propenyl 11.4 → 1.3 5.29 → 28.6 1,590 → 54
11w→75l cis-propenyl 7.09 → 1.15 15 → 31.6 2,800 → 147
11x→75 m Allyl 28.4 → 6.2 32.8 → 56.5 2,480 → 89.7
11z→75o 1-Propynyl 15.7 → 3.16 2.37 → 6.11 820 → 116
11s→75h i-Propyl 191 → 15.1 597 → 310 75,000 → ?
11u→75j 2-Propenyl 3.13 → 0.6 14.4 → 23 1,330? → 144
N-Demethylating phenyltropanes to find a NRI
Isomer 4′ 3′ NE DA 5HT
β,β Me H 60 → 7.2 1.7 → 0.84 240 → 135
β,β F H 835 → 18.8 15.7 → 4.4 760 → 68.6
β,β Cl H 37 → 5.45 1.12 → 0.62 45 → 4.13
β,α Me H 270 → 9 10.2 → 33.6 4250 → 500
β,α F H 1200 → 9.8 21 → 32.6 5060 → 92.4
β,α Cl H 60 → 5.41 2.4 → 3.1 998 → 53.3
β,α F Me 148 → 4.23 13.7 → 9.38 1161 → 69.8
β,α Me F 44.7 → 0.86 7.38 → 9 1150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).[35]

N-norphenyltropanes[1]
Structure Short Name
(S. Singh) 		Para-X DAT
[3H]WIN 35428 IC50 (nM) 		5-HTT
[3H]Paroxetine IC50 (nM) 		NET
[3H]Nisoxetine IC50 (nM) 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
Norcocaine H 206 ± 29 127 ± 13 139 ± 9 0.6 0.7
75a H 30.8 ± 2.3 156 ± 8 84.5 ± 7.5 5.1 2.7
75b F 4.39 ± 0.20 68.6 ± 2.0 18.8 ± 0.7 15.6 4.3
75c Cl 0.62 ± 0.09 4.13 ± 0.62 5.45 ± 0.21 6.7 8.8
75d I 0.69 ± 0.2 0.36 ± 0.05 7.54 ± 3.19 0.5 10.9
75e para-I
&
2β-CO2CH(CH3)2		 1.06 ± 0.12 3.59 ± 0.27 132 ± 5 3.4 124
75f C2H5 49.9 ± 7.3 8.13 ± 0.30 122 ± 12 0.2 2.4
75g n-C3H7 212 ± 17 26 ± 1.3 532 ± 8.1 0.1 2.5
75h CH(CH3)2 310 ± 21 15.1 ± 0.97 - 0.05 -
75i CH=CH2 1.73 ± 0.05 2.25 ± 0.17 14.9 ± 1.18 1.3 8.6
75j C-CH3
║
CH2		 23 ± 0.9 0.6 ± 0.06 144 ± 12 0.03 6.3
75k trans-CH=CHCH3 28.6 ± 3.1 1.3 ± 0.1 54 ± 16 0.04 1.9
75l cis-CH=CHCH3 31.6 ± 2.2 1.15 ± 0.1 147 ± 4.3 0.04 4.6
75m CH2CH=CH2 56.5 ± 56 6.2 ± 0.3 89.7 ± 9.6 0.1 1.6
75n CH≡CH 1.24 ± 0.11 1.59 ± 0.2 21.8 ± 1.0 1.3 17.6
75o CH≡CCH3 6.11 ± 0.67 3.16 ± 0.33 116 ± 5.1 0.5 19.0
75pɑ 3,4-Cl2 0.66 ± 0.24 1.4b - 2.1 -

ɑThese values determined in Cynomolgus monkey caudate-putamen bThe radioligand used for 5-HTT was [3H]citalopram

2β-Propanoyl-N-norphenyltropanes[1]
Compound Structure Short Name
(S. Singh) 		DAT
[125I]RTI-55 IC50 (nM) 		5-HTT
[3H]Paroxetine Ki (nM) 		NET
[3H]Nisoxetine Ki (nM) 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
79a 0.07 ± 0.01 0.22 ± 0.16 2.0 ± 0.09 3.1 28.6
79b 4.7 ± 0.58 19 ± 1.4 5.5 ± 2.0 4.0 1.2
79c 380 ± 110 5.3 ± 1.0 3400 ± 270 0.01 8.9
79d 190 ± 17 150 ± 50 5100 ± 220 0.8 26.8
79e 490 ± 120 85 ± 16 4300 ± 1100 0.1 8.8
79f 1.5 ± 1.1 0.32 ± 0.06 10.9 ± 1.5 0.2 7.3
79g 16 ± 4.9 0.11 ± 0.02 94 ± 18 0.07 5.9

Paroxetine homologues[edit]

See the N-methyl paroxetine homologues cf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.

2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies[1]
Compound Structure Short Name
(S. Singh) 		Stereochemistry DAT
[3H]WIN 35428 IC50 (nM) 		5-HTT
[3H]Paroxetine IC50 (nM) 		NET
[3H]Nisoxetine IC50 (nM) 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
Paroxetine - 623 ± 25 0.28 ± 0.02 535 ± 15 0.0004 0.8
R-81a 2β,3β 835 ± 90 480 ± 21 37400 ± 1400 0.6 44.8
R-81b 2α,3β 142 ± 13 90 ± 3.4 2500 ± 250 0.6 17.6
R-81c 2β,3α 3.86 ± 0.2 5.62 ± 0.2 14.4 ± 1.3 1.4 3.7
S-81d 2β,3β 1210 ± 33 424 ± 15 17300 ± 1800 0.3 14.3
S-81e 2α,3β 27.6 ± 2.4 55.8 ± 5.73 1690 ± 150 2.0 61.2
S-81f 2β,3α 407 ± 33 19 ± 1.8 1990 ± 176 0.05 4.9

N-replaced (S,O,C)[edit]

R-97a (above) & S-97b (below), both examples of interm. synth. prod. in the R/S-90 & 91 series of phenyltropanes; showing the decay of the benzene structure during the synthetic process preceding the creation of like-series of PTs.[1]

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

Compound X 2 Group config 8 DA 5-HT NE
Tropoxane Cl,Cl CO2Me (racemic) β,β O 3.3 6.5 No data
O-4210[36] p-F 3-methyl-5-isoxazole β,β S 7.0 >1000 No data
Mid-synth stage in similar compound preparation as like to above.

8-oxa bridgehead replacements[edit]

8-Oxanortropanes, binding inhibition using monkey caudate-putamen[1]
Structure Compound #
(S. Singh) 		Para-
(meta-) 		DAT (IC50 nM)
displacement of [H3]WIN 35428 		5-HTT (IC50 nM)
[H3]Citalopram 		Selectivity
5-HTT/DAT
R/S-90a H >1000 >1000 -
R/S-90b F 546 2580 4.7
R/S-90c Cl 10 107 10.7
R/S-90d Br 22 30 1.4
R/S-90e I 7 12 1.7
R/S-90f 3,4-Cl2 3.35 6.52 1.9
R-90g 3,4-Cl2 3.27 4.67 1.4
S-90h 3,4-Cl2 47 58 1.2
R/S-91a H 1990 11440 5.7
R/S-91b F >1000 >10000 -
R/S-91c Cl 28.5 816 28.6
R/S-91d Br 9 276 30.7
R/S-91e I 42 72 1.7
R/S-91f 3,4-Cl2 3.08 64.5 20.9
R-91g 3,4-Cl2 2.34 31 13.2
S-91h 3,4-Cl2 56 2860 51.1

8-carba bridgehead replacements[edit]

8-carba 3-Aryl bicyclo[3.2.1]octanes[1]
Structure Compound #
(S. Singh) 		DAT (IC50 nM)
displacement of [H3]WIN 35428 		5-HTT (IC50 nM)
[H3]Citalopram 		Selectivity
5-HTT/DAT
R/S-98a 7.1 ± 1.7 5160 ± 580 726
R/S-98b 9.6 ± 1.8 33.4 ± 0.6 3.5
R/S-98c 14.3 ± 1.1 180 ± 65 12.6

N-alkyl[edit]

Compound X 2 Group config 8 DAT SERT NET
FP-β-CPPIT Cl 3′-phenylisoxazol-5′-yl β,β NCH2CH2CH2F - - -
FE-β-CPPIT Cl (3′-phenylisoxazol-5′-yl) β,β NCH2CH2F - - -
Altropane (IACFT) F CO2Me β,β NCH2CH=CHF - - -
FECNT[37] I CO2Me β,β NCH2CH2F - - -
RTI-310 U.S. patent 5,736,123 I CO2Me β,β N-Prn 1.17 - -
RTI-311 I CO2Me β,β NCH2CH=CH2 1.79 - -
RTI-312 U.S. patent 5,736,123 I CO2Me β,β NBun 0.76 - -
RTI-313 U.S. patent 5,736,123 I CO2Me β,β NCH2CH2CH2F 1.67 - -
Ioflupane (FP-CIT) 123I CO2Me β,β NCH2CH2CH2F - - -
PE2I[37] Me CO2Me β,β NCH2CH=CHI - - -
RTI-251 Cl CO2Me β,β NCH2CO2Et 1.93 10.1 114
RTI-252 Cl CO2Me β,β NCH2CH2CO2Et 2.56 35.2 125
RTI-242 Cl β,β (bridged) -C(O)CH(CO2Me)CH2N 7.67 227 510

Bi- and tri-cyclic aza compounds and their uses.[38][39]

N-substituted 3β-phenylnortropanes[1]
(including N-phthalimidoalkyl analogues of β-CIT)
Structure Short Name
(S. Singh) 		Nitrogen side-chain
(N8) 		DAT
[3H]GBR 12935 Ki (nM) 		5-HTT
[3H]Paroxetine Ki (nM) 		NET
[3H]Nisoxetine Ki (nM) 		Selectivity
5-HTT/DAT 		Selectivity
NET/DAT
Cocaine H 350 ± 80 >10000 >30000 >28.6 -
GBR 12909 - 0.06 ± 0.02 52.8 ± 4.4 >20000 880 -
WIN 35428
11b		 H 14.7 ± 2.9 181 ± 21 635 ± 110 12.3 43.2
RTI-55
11e		 H 1.40 ± 0.20 0.46 ± 0.06 2.80 ± 0.40 0.3 2
82a CH2CH=CH2 22.6 ± 2.9ɑ - - - -
82b CH2CH2CH3 43.0 ± 17.7ɑ - - - -
82c CH2C6H5 58.9 ± 1.65b 1073c - 18.2 -
82d (CH2)3C6H5 1.4 ± 0.2b 133 ± 7c - 95.0 -
82e (CH2)5C6H5 3.4 ± 0.83b 49.9 ± 10.2c - 14.7 -
83a CH2CH2CH2F 1.20 ± 0.29 48.7 ± 8.4 10000 40.6 8333
83b CH2CH2F 4.40 ± 0.35 21.7 ± 8.3 >10000 4.9 -
84a CH2CH2CH2F 3.50 ± 0.39 0.110 ± 0.02 63.0 ± 4.0 0.03 18
84b CH2CH2F 4.00 ± 0.73 0.140 ± 0.02 93.0 ± 17.0 0.03 23.2
84c CH2CHF2 15.1 ± 3.7 9.6 ± 1.5 >5000 0.6 -
84d CH2CH2CH2Cl 3.10 ± 0.57 0.32 ± 0.06 96.0 ± 29.0 0.1 31.0
84e CH2CH2CH2Br 2.56 ± 0.57 0.35 ± 0.08 164 ± 47 0.1 64.1
84f CH2CH2CH2I 38.9 ± 6.3 8.84 ± 0.53 5000 0.2 128
84g CH2...methylcyclopropane 4.30 ± 0.87 1.30 ± 0.25 198 ± 9.6 0.3 46.0
84h CH2CH2CH2OH 5.39 ± 0.21 2.50 ± 0.20 217 ± 19 0.5 40.2
84i CH2CH2(OCH3)2 6.80 ± 1.10 1.69 ± 0.09 110 ± 7.7 0.2 16.2
84j CH2CO2CH3 11.9 ± 1.4 0.81 ± 0.10 29.1 ± 1.0 0.07 2.4
84k CH2CON(CH3)2 12.2 ± 3.8 6.40 ± 1.70 522 ± 145 0.5 42.8
84l CH2CH2CH2OMs 36.3 ± 2.1 17.3 ± 1.2 5000 0.5 138
84m COCH(CH3)2 2100 ± 140 102 ± 23 >10000 0.05 -
84n (CH2)2Pht 4.23 ± 0.48 0.84 ± 0.02 441 ± 66.0 0.2 104
84o (CH2)3Pht 9.10 ± 1.10 0.59 ± 0.07 74.0 ± 11.6 0.06 8.1
84p (CH2)4Pht 2.38 ± 0.22 0.21 ± 0.02 190 ± 18.0 0.09 79.8
84q (CH2)5Pht 2.40 ± 0.17 0.34 ± 0.03 60.0 ± 3.10 0.1 25.0
84r (CH2)8Pht 2.98 ± 0.30 0.20 ± 0.02 75.0 ± 3.6 0.07 25.2
84sd CH2CH=CH-CH3 15 ± 1 75 ± 5 400 ± 80 5.0 26.7
84td CH2C(Br)=CH2 30 ± 5 200 ± 40 >1000 6.7 -
84ud CH2CH=CH2I(E) 30 ± 5 960 ± 60 295 ± 33 32.0 9.8
84vd CH2C≡CH 14 ± 1 100 ± 30 >1000 7.1 -
84wd CH2C6H5 42 ± 12 100 ± 17 600 ± 100 2.4 14.3
84xd CH2C6H4-2-CH3 93 ± 19 225 ± 40 >1000 2.4 -
85ad para-H 113 ± 41 100 ± 20 >1000 0.9 -
85bd para-Cl, meta-Cl 29 ± 4 50 ± 6 500 ± 120 1.7 17.2
85cd para-Me 17 ± 7 500 ± 30 >1000 29.4 -
85dd para-CH(CH3)2 500 ± 120 450 ± 80 >1000 0.9 -
85ed para-n-C3H7 500 ± 100 300 ± 12 750 ± 160 0.6 1.5
  • ɑIC50 for displacement of [3H]cocaine. IC50 for cocaine = 67.8 ± 8.7 (nM)
  • bIC50 values for displacement of [3H]WIN 35428
  • cIC50 values for displacement of [3H]citalopram
  • dThe standard Ki value for the displacement of [3H]GBR 12935, [3H]paroxetine, and [3H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments
3β-(4-alkylthiophenyl)nortropanes[12]
Structure Compound R1 R2 Inhibition of [3H]WIN 35,428
@ DAT
IC50 (nM) 		Inhibition of [3H]Paroxetine
@ 5-HTT
Ki (nM) 		Inhibition of [3H]Nisoxetine
@ NET
Ki (nM) 		NET/DAT
(uptake ratio) 		NET/5-HTT
(uptake ratio)
See 7a—7h table
7a CH3 CH3 9 ± 3 0.7 ± 0.2 220 ± 10 24 314
7b C2H5 CH3 232 ± 34 4.5 ± 0.5 1170 ± 300 5 260
8a CH3 H 28 ± 6 0.19 ± 0.01 21 ± 6 0.8 110
8b C2H5 H 177 ± 62 1.26 ± 0.05 118 ± 13 0.7 94
9a CH3 FCH2CH2CH2<

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