Nemonapride

Last updated
Nemonapride
Nemonapride.svg
Clinical data
Trade names Emilace ( JP , CN )
Other namesEmonapride; Emirace; YM 09151-2; YM09151-2; YM 09151; YM09151
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral [1] [2]
Drug class Dopamine 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
Metabolism Primarily CYP3A4 [2]
Elimination half-life 2.3–4.5 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
Formula C21H26ClN3O2
Molar mass 387.91 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]

Contents

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 Tooltip 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

Names

Nemonapride is the generic name of the drug and its INN Tooltip International Nonproprietary Name and JAN Tooltip 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 (JP Tooltip Japanese language: 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

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References

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  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "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. 1 2 "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. 1 2 "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. 1 2 3 4 Burke, A.J.; Marques, C.S.; Turner, N.J.; Hermann, G.J. (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. 1 2 3 4 5 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 845. ISBN   978-3-88763-101-7 . Retrieved 24 October 2024.
  8. 1 2 3 4 5 https://web.archive.org/web/20160303233759/https://drugs.com/international/nemonapride.html
  9. ↑ MacDonald GJ, Bartolomé JM (2010). "A decade of progress in the discovery and development of 'atypical' antipsychotics". Prog Med Chem. 49: 37–80. doi:10.1016/S0079-6468(10)49002-5. 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. 1 2 Iwanami, Sumio; Takashima, Mutsuo; Hirata, Yasufumi; Hasegawa, Osamu; Usuda, Shinji (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. ISSN   0022-2623.
  14. ↑ Harada, Shingo; Sakai, Takeo; Takasu, Kiyosei; Yamada, Ken-ichi; Yamamoto, Yasutomo; Tomioka, Kiyoshi (2012-08-20). "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. ISSN   0022-3263.
  15. ↑ Uesugi, Shun-ichiro; Sasano, Yusuke; Matsui, Shogo; Kanoh, Naoki; Iwabuchi, Yoshiharu (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 . ISSN   0009-2363.
  16. ↑ USUDA, S., & MAENO, H. (1980, January). PHARMACOLOGICAL PROPERTIES OF A NEW BENZAMIDE, YM-09151-2 WITH POTENTIALLY NEUROLEPTIC ACTIONS. In FOLIA PHARMACOLOGICA JAPONICA (Vol. 76, No. 7, pp. P184-P185).
  17. ↑ Mori, A., Kazamatsuri, H., Kaneno, S., Kamijima, K., Kariya, T., Murasaki, M., & Yagi, G. (1989). A double-bind comparison of a new benzamide compound YM-09151 (Nemonapride) with haloperidol in the treatment of schizophrenia. Clin Eval 17: 349, 77. https://scholar.google.com/scholar?cluster=14939639320629959642
  18. ↑ https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/rl31.pdf
  19. 1 2 3 Morton, I.K.; Hall, J.M. (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 191. ISBN   978-94-011-4439-1 . Retrieved 24 October 2024.
  20. ↑ https://iris.who.int/bitstream/handle/10665/379226/9789240099388-eng.pdf#page=173
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