Chemistry:Nemonapride

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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

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

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

Side effects

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

Pharmacology

Pharmacodynamics

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

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

Chemistry

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

Structure and stereochemistry

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

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 INN 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

Names

Nemonapride is the generic name of the drug and its INN and JAN.[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 (JP: エミレース) in Japan and China.[8][7][19]

Availability

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

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 "Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability". Drugs 68 (16): 2269–2292. 2008. doi:10.2165/0003495-200868160-00002. PMID 18973393. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 "医療用医薬品 : エミレース (エミレース錠3mg 他)" (in ja). 18 September 2024. https://www.kegg.jp/medicus-bin/japic_med?japic_code=00060312. 
  3. ↑ 3.0 3.1 "Nemonapride". 6 June 2007. https://adisinsight.springer.com/drugs/800007270. 
  4. ↑ "Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis". Psychiatry and Clinical Neurosciences (Wiley) 69 (5): 243–258. May 2015. doi:10.1111/pcn.12242. PMID 25296946. 
  5. ↑ 5.0 5.1 "Pharmaceuticals and Medical Devices Safety Information No. 265". Pharmaceuticals and Medical Devices Agency. January 2010. https://www.pmda.go.jp/files/000153478.pdf. 
  6. ↑ 6.0 6.1 6.2 6.3 Active Pharmaceutical Ingredients in Synthesis: Catalytic Processes in Research and Development. Wiley. 2018. p. 380. ISBN 978-3-527-34241-9. https://books.google.com/books?id=HLBlDwAAQBAJ&pg=PA380. Retrieved 24 October 2024. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 845. ISBN 978-3-88763-101-7. https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA845. Retrieved 24 October 2024. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Nemonapride". Drugs.com. https://drugs.com/international/nemonapride.html. 
  9. ↑ "A decade of progress in the discovery and development of 'atypical' antipsychotics". Prog Med Chem. Progress in Medicinal Chemistry 49: 37–80. 2010. doi:10.1016/S0079-6468(10)49002-5. ISBN 978-0-12-381292-6. PMID 20855038. 
  10. ↑ "Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties". Psychopharmacology (Berl) 216 (4): 451–473. August 2011. doi:10.1007/s00213-011-2247-y. PMID 21394633. 
  11. ↑ "5-HT1A receptor agonist properties of the antipsychotic, nemonapride: comparison with bromerguride and clozapine". Eur J Pharmacol 334 (2–3): 141–147. September 1997. doi:10.1016/s0014-2999(97)01207-7. PMID 9369342. 
  12. ↑ "Dopamine D2 and D4 receptor ligands: relation to antipsychotic action". Eur J Pharmacol 351 (3): 273–286. June 1998. doi:10.1016/s0014-2999(98)00312-4. PMID 9721018. 
  13. ↑ 13.0 13.1 "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 (American Chemical Society (ACS)) 24 (10): 1224–1230. October 1981. doi:10.1021/jm00142a019. PMID 6120234. 
  14. ↑ "General entry to asymmetric one-pot [N + 2 + n] cyclization for the synthesis of three- to seven-membered azacycloalkanes". The Journal of Organic Chemistry (American Chemical Society (ACS)) 77 (17): 7212–7222. September 2012. doi:10.1021/jo301495a. PMID 22894619. 
  15. ↑ "Concise, Protecting-Group-Free Synthesis of (+)-Nemonapride via Eu(OTf)3-Catalyzed Aminolysis of 3,4-Epoxy Alcohol". Chemical & Pharmaceutical Bulletin (Pharmaceutical Society of Japan) 65 (1): 22–24. 2017. doi:10.1248/cpb.c16-00568. PMID 28049911. 
  16. ↑ "Pharmacological Properties of a New Benzamide, YM-09151-2 With Potentially Neuroleptic Actions.". Infolia Pharmacologica Japonica (Japan: Japanese Pharmacological Soc.) 76 (7): 184–185. January 1980. 
  17. ↑ "A double-blind comparison of a new benzamide compound YM-09151 with haloperidol in the treatment of schizophrenia.". Clin Eval. 17: 349–377. 1989. 
  18. ↑ "International Nonproprietary Names for Pharmaceutical Substances". WHO Drug Information 5 (3). 1991. https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/rl31.pdf. 
  19. ↑ 19.0 19.1 19.2 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. 2012. p. 191. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA191. Retrieved 24 October 2024. 
  20. ↑ "-pride: sulpiride derivatives and analogues". Use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. World Health Organization (WHO). 2024. https://iris.who.int/bitstream/handle/10665/379226/9789240099388-eng.pdf#page=173. 



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