Nemonapride

Nemonapride
Clinical data
Trade namesEmilace (JP, CN)
Other namesEmonapride; Emirace; YM 09151-2; YM09151-2; YM 09151; YM09151
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral[1][2]
Drug classDopamine D2, D3, and D4 receptor antagonist; Serotonin 5-HT1A receptor partial agonist; Antipsychotic
ATC code
  • None
Legal status
Legal status
  • Rx-only (JP)
Pharmacokinetic data
MetabolismPrimarily CYP3A4[2]
Elimination half-life2.3–4.5 hours[2]
Identifiers
  • N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H26ClN3O2
Molar mass387.91 g·mol−1
3D model (JSmol)
  • CC1C(CCN1CC2=CC=CC=C2)NC(=O)C3=CC(=C(C=C3OC)NC)Cl
  • InChI=1S/C21H26ClN3O2/c1-14-18(9-10-25(14)13-15-7-5-4-6-8-15)24-21(26)16-11-17(22)19(23-2)12-20(16)27-3/h4-8,11-12,14,18,23H,9-10,13H2,1-3H3,(H,24,26)
  • Key:KRVOJOCLBAAKSJ-UHFFFAOYSA-N
  (verify)

Nemonapride, also previously known as emonapride and sold under the brand name Emilace, is an atypical antipsychotic which is used in the treatment of schizophrenia.[1][2][3] It is taken by mouth.[1][2]

Side effects of nemonapride include akathisia, dystonia, hypokinesia, tremor, hypersalivation, and hyperprolactinemia, among others.[1][2] The drug acts as a dopamine D2, D3, and D4 receptor antagonist.[1] To a lesser extent, it is also a serotonin 5-HT1A receptor partial agonist.[4] Structurally, nemonapride is a benzamide derivative and is related to sulpiride and other benzamides.[1]

Nemonapride was introduced for medical use in either 1991[5] or 1997.[1][6] It was developed and marketed by Yamanouchi Pharmaceuticals.[6][7] The drug is approved only in Japan and China.[8]

Medical uses

[edit]

Nemonapride is used in the treatment of schizophrenia.[1][2] It is described as being effective in treating the positive symptoms of schizophrenia.[1] It is also said to have some antidepressant and anxiolytic effects.[1] However, clinical data on nemonapride are described as being somewhat limited.[1]

Available forms

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Nemonapride is available in the form of 3 and 10 mg oral tablets.[2]

Side effects

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Side effects of nemonapride include akathisia, dystonia, hypokinesia, tremor, hypersalivation, and hyperprolactinemia, among others.[1][2]

Pharmacology

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Pharmacodynamics

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Nemonapride has been described both as a typical antipsychotic[1] and as an atypical antipsychotic.[9] It is a potent and selective dopamine D2, D3, and D4 receptor antagonist.[1] Its affinities (Ki) for these receptors are 0.16 nM for the dopamine D2 receptor, 0.26 nM for the dopamine D3 receptor, and 0.31 nM for the dopamine D4 receptor.[1] Antagonism of the dopamine D2 receptor is thought to be responsible for the antipsychotic effects of nemonapride.[2]

In addition to the dopamine D2-like receptors, nemonapride has weaker affinity for the serotonin 5-HT1A and 5-HT2A receptors.[1] Its affinities (Ki) for these receptors are 1.8 nM for the serotonin 5-HT1A receptor (11-fold lower than for the D2 receptor) and 9.4 nM for the serotonin 5-HT2A receptor (59-fold lower than for the D2 receptor).[1] It is a partial agonist of the serotonin 5-HT1A receptor.[10][1][11] It has very weak affinity for sigma receptors (Ki = 80–3,000 nM) as well.[12] Besides these specific receptors, nemonapride is described as having very weak affinity for the dopamine D1, serotonin 5-HT2, adrenergic, and cholinergic receptors.[1]

In animals, nemonapride suppresses conditioned avoidance responses, inhibits methamphetamine- and apomorphine-induced hyperactivity and stereotypy, produces catalepsy, and has slight central depressant effects.[1][2]

Pharmacokinetics

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Nemonapride is metabolized primarily by the cytochrome P450 enzyme CYP3A4.[2] Its elimination half-life is 2.3 to 4.5 hours.[2]

Chemistry

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Nemonapride is a benzamide derivative and is structurally related to other dopamine antagonists of the benzamide group such as sulpiride.[1]

Structure and stereochemistry

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Nemonapride is a cis-2-methyl-3-amino-pyrrolidine derivative,[13] which was later shown to express most of its action as a drug to treat schizophrenia from its homochiral (+)-(2R,3R) form.[14][15]

History

[edit]

Nemonapride was developed by scientists at Yamanouchi Pharmaceuticals via structural modification of the benzamide antiemetic and gastroprokinetic agent metoclopramide.[6][13] It was first described in the scientific literature by 1980.[16] The name nemonapride was first used by 1989 and this name was designated as its INNTooltip International Nonproprietary Name in 1991.[17][18] The drug was launched in May 1991.[5] However, other sources state that it was launched in 1997.[1][6]

Society and culture

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Names

[edit]

Nemonapride is the generic name of the drug and its INNTooltip International Nonproprietary Name and JANTooltip Japanese Accepted Name.[8][7][19] It was also previously known as emonapride and by its former developmental code name YM 09151-2.[8][7][19][20] In addition, nemonapride is known by its brand name Emilace (JPTooltip Japanese language: エミレース) in Japan and China.[8][7][19]

Availability

[edit]

Nemonapride is marketed only in Japan and China.[8][7] It was also under development for use in other countries, such as France, but development in other countries was discontinued.[3][1] There are no further plans for nemonapride to be developed for use in the United States, the United Kingdom, or Europe.[1]

See also

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References

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  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x Bishara D, Taylor D (2008). "Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability". Drugs. 68 (16): 2269–2292. doi:10.2165/0003495-200868160-00002. PMID 18973393.
  2. ^ a b c d e f g h i j k l m "医療用医薬品 : エミレース (エミレース錠3mg 他)". KEGG (in Japanese). 18 September 2024. Retrieved 24 October 2024.
  3. ^ a b "Nemonapride". AdisInsight. 6 June 2007. Retrieved 24 October 2024.
  4. ^ Kusumi I, Boku S, Takahashi Y (May 2015). "Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis". Psychiatry and Clinical Neurosciences. 69 (5). Wiley: 243–258. doi:10.1111/pcn.12242. PMID 25296946. S2CID 23102204.
  5. ^ a b "Pharmaceuticals and Medical Devices Safety Information No. 265" (PDF). Pharmaceuticals and Medical Devices Agency. January 2010. Archived from the original (PDF) on 26 July 2022. Retrieved 26 July 2022.
  6. ^ a b c d Burke A, Marques C, Turner N, Hermann G (2018). Active Pharmaceutical Ingredients in Synthesis: Catalytic Processes in Research and Development. Wiley. p. 380. ISBN 978-3-527-34241-9. Retrieved 24 October 2024.
  7. ^ a b c d e Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 845. ISBN 978-3-88763-101-7. Retrieved 24 October 2024.
  8. ^ a b c d e "Nemonapride". Drugs.com. Archived from the original on 2016-03-03.
  9. ^ MacDonald GJ, Bartolomé JM (2010). "A decade of progress in the discovery and development of 'atypical' antipsychotics". Prog Med Chem. Progress in Medicinal Chemistry. 49: 37–80. doi:10.1016/S0079-6468(10)49002-5. ISBN 978-0-12-381292-6. PMID 20855038.
  10. ^ Newman-Tancredi A, Kleven MS (August 2011). "Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties". Psychopharmacology (Berl). 216 (4): 451–473. doi:10.1007/s00213-011-2247-y. PMID 21394633.
  11. ^ Assié MB, Cosi C, Koek W (September 1997). "5-HT1A receptor agonist properties of the antipsychotic, nemonapride: comparison with bromerguride and clozapine". Eur J Pharmacol. 334 (2–3): 141–147. doi:10.1016/s0014-2999(97)01207-7. PMID 9369342.
  12. ^ Wilson JM, Sanyal S, Van Tol HH (June 1998). "Dopamine D2 and D4 receptor ligands: relation to antipsychotic action". Eur J Pharmacol. 351 (3): 273–286. doi:10.1016/s0014-2999(98)00312-4. PMID 9721018.
  13. ^ a b Iwanami S, Takashima M, Hirata Y, Hasegawa O, Usuda S (October 1981). "Synthesis and neuroleptic activity of benzamides. Cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide and related compounds". Journal of Medicinal Chemistry. 24 (10). American Chemical Society (ACS): 1224–1230. doi:10.1021/jm00142a019. PMID 6120234.
  14. ^ Harada S, Sakai T, Takasu K, Yamada K, Yamamoto Y, Tomioka K (September 2012). "General entry to asymmetric one-pot [N + 2 + n] cyclization for the synthesis of three- to seven-membered azacycloalkanes". The Journal of Organic Chemistry. 77 (17). American Chemical Society (ACS): 7212–7222. doi:10.1021/jo301495a. PMID 22894619.
  15. ^ Uesugi SI, Sasano Y, Matsui S, Kanoh N, Iwabuchi Y (2017). "Concise, Protecting-Group-Free Synthesis of (+)-Nemonapride via Eu(OTf)3-Catalyzed Aminolysis of 3,4-Epoxy Alcohol". Chemical & Pharmaceutical Bulletin. 65 (1). Pharmaceutical Society of Japan: 22–24. doi:10.1248/cpb.c16-00568. PMID 28049911.
  16. ^ Usuda S, Maeno H (January 1980). "Pharmacological Properties of a New Benzamide, YM-09151-2 With Potentially Neuroleptic Actions". Infolia Pharmacologica Japonica. 76 (7). Japan: Japanese Pharmacological Soc.: 184–185.
  17. ^ Mori A, Kazamatsuri H, Kaneno S, Kamijima K, Kariya T, Murasaki M, et al. (1989). "A double-blind comparison of a new benzamide compound YM-09151 with haloperidol in the treatment of schizophrenia". Clin Eval. 17: 349–377.
  18. ^ "International Nonproprietary Names for Pharmaceutical Substances" (PDF). WHO Drug Information. 5 (3). 1991.
  19. ^ a b c Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 191. ISBN 978-94-011-4439-1. Retrieved 24 October 2024.
  20. ^ "-pride: sulpiride derivatives and analogues" (PDF). Use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. World Health Organization (WHO). 2024.
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