nemonapride

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

Nemonapride is available in the form of 3 and 10{{nbsp}}mg oral tablets.

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

Nemonapride has been described both as a typical antipsychotic and as an atypical antipsychotic.{{cite journal | vauthors = MacDonald GJ, Bartolomé JM | title = A decade of progress in the discovery and development of 'atypical' antipsychotics | journal = Prog Med Chem | series = Progress in Medicinal Chemistry | volume = 49 | issue = | pages = 37–80 | date = 2010 | pmid = 20855038 | doi = 10.1016/S0079-6468(10)49002-5 | isbn = 978-0-12-381292-6 | url = }} It is a potent and selective dopamine D₂, D₃, and D₄ receptor antagonist. Its affinities (K_i) for these receptors are 0.16{{nbsp}}nM for the dopamine D₂ receptor, 0.26{{nbsp}}nM for the dopamine D₃ receptor, and 0.31{{nbsp}}nM for the dopamine D₄ receptor. Antagonism of the dopamine D₂ receptor is thought to be responsible for the antipsychotic effects of nemonapride.

In addition to the dopamine D₂-like receptors, nemonapride has weaker affinity for the serotonin 5-HT_1A and 5-HT_2A receptors. Its affinities (K_i) for these receptors are 1.8{{nbsp}}nM for the serotonin 5-HT_1A receptor (11-fold lower than for the D₂ receptor) and 9.4{{nbsp}}nM for the serotonin 5-HT_2A receptor (59-fold lower than for the D₂ receptor). It is a partial agonist of the serotonin 5-HT_1A receptor.{{cite journal | vauthors = Newman-Tancredi A, Kleven MS | title = Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties | journal = Psychopharmacology (Berl) | volume = 216 | issue = 4 | pages = 451–473 | date = August 2011 | pmid = 21394633 | doi = 10.1007/s00213-011-2247-y | url = }}{{cite journal | vauthors = Assié MB, Cosi C, Koek W | title = 5-HT1A receptor agonist properties of the antipsychotic, nemonapride: comparison with bromerguride and clozapine | journal = Eur J Pharmacol | volume = 334 | issue = 2–3 | pages = 141–147 | date = September 1997 | pmid = 9369342 | doi = 10.1016/s0014-2999(97)01207-7 | url = }} It has very weak affinity for sigma receptors (K_i = 80–3,000{{nbsp}}nM) as well.{{cite journal | vauthors = Wilson JM, Sanyal S, Van Tol HH | title = Dopamine D2 and D4 receptor ligands: relation to antipsychotic action | journal = Eur J Pharmacol | volume = 351 | issue = 3 | pages = 273–286 | date = June 1998 | pmid = 9721018 | doi = 10.1016/s0014-2999(98)00312-4 | url = }} Besides these specific receptors, nemonapride is described as having very weak affinity for the dopamine D₁, serotonin 5-HT₂, adrenergic, and cholinergic receptors.

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

Nemonapride is metabolized primarily by the cytochrome P450 enzyme CYP3A4. Its elimination half-life is 2.3 to 4.5{{nbsp}}hours.

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

Nemonapride is a cis-2-methyl-3-amino-pyrrolidine derivative, which was later shown to express most of its action as a drug to treat schizophrenia from its homochiral (+)-(2R,3R) form.{{cite journal | vauthors = Harada S, Sakai T, Takasu K, Yamada K, Yamamoto Y, Tomioka K | title = General entry to asymmetric one-pot [N + 2 + n] cyclization for the synthesis of three- to seven-membered azacycloalkanes | journal = The Journal of Organic Chemistry | volume = 77 | issue = 17 | pages = 7212–7222 | date = September 2012 | pmid = 22894619 | doi = 10.1021/jo301495a | publisher = American Chemical Society (ACS) }}{{cite journal | vauthors = Uesugi SI, Sasano Y, Matsui S, Kanoh N, Iwabuchi Y | title = Concise, Protecting-Group-Free Synthesis of (+)-Nemonapride via Eu(OTf)₃-Catalyzed Aminolysis of 3,4-Epoxy Alcohol | journal = Chemical & Pharmaceutical Bulletin | volume = 65 | issue = 1 | pages = 22–24 | year = 2017 | pmid = 28049911 | doi = 10.1248/cpb.c16-00568 | publisher = Pharmaceutical Society of Japan | doi-access = free }}

Nemonapride was developed by scientists at Yamanouchi Pharmaceuticals via structural modification of the benzamide antiemetic and gastroprokinetic agent metoclopramide.{{cite journal | vauthors = Iwanami S, Takashima M, Hirata Y, Hasegawa O, Usuda S | title = 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 = Journal of Medicinal Chemistry | volume = 24 | issue = 10 | pages = 1224–1230 | date = October 1981 | pmid = 6120234 | doi = 10.1021/jm00142a019 | publisher = American Chemical Society (ACS) }} It was first described in the scientific literature by 1980.{{cite journal | vauthors = Usuda S, Maeno H | title = Pharmacological Properties of a New Benzamide, YM-09151-2 With Potentially Neuroleptic Actions. | journal = Infolia Pharmacologica Japonica | date = January 1980 | volume = 76 | issue = 7 | pages = 184–185 | location = Japan | publisher = Japanese Pharmacological Soc. }} The name nemonapride was first used by 1989 and this name was designated as its {{Abbrlink|INN|International Nonproprietary Name}} in 1991.{{cite journal | vauthors = Mori A, Kazamatsuri H, Kaneno S, Kamijima K, Kariya T, Murasaki M, Yagi G | title = A double-blind comparison of a new benzamide compound YM-09151 with haloperidol in the treatment of schizophrenia. | journal = Clin Eval. | date = 1989 | volume = 17 | pages = 349–377 }}{{cite journal | title = International Nonproprietary Names for Pharmaceutical Substances | journal = WHO Drug Information | volume = 5 | issue = 3 | date = 1991 | url = https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/rl31.pdf }} The drug was launched in May 1991.{{cite web |title=Pharmaceuticals and Medical Devices Safety Information No. 265 |url=https://www.pmda.go.jp/files/000153478.pdf |publisher=Pharmaceuticals and Medical Devices Agency |access-date=26 July 2022 |archive-url=https://web.archive.org/web/20220726232009/https://www.pmda.go.jp/files/000153478.pdf |archive-date=26 July 2022 |date=January 2010}} However, other sources state that it was launched in 1997.

Nemonapride is the generic name of the drug and its {{Abbrlink|INN|International Nonproprietary Name}} and {{Abbrlink|JAN|Japanese Accepted Name}}.{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA845 | access-date=24 October 2024 | page=845}}{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA191 | access-date=24 October 2024 | page=191}} It was also previously known as emonapride and by its former developmental code name YM 09151-2.{{cite book | chapter = -pride: sulpiride derivatives and analogues | title = Use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances | date = 2024 | chapter-url = https://iris.who.int/bitstream/handle/10665/379226/9789240099388-eng.pdf#page=173 | publisher = World Health Organization (WHO) }} In addition, nemonapride is known by its brand name Emilace ({{Abbrlink|JP|Japanese language}}: エミレース) in Japan and China.

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

• ENX-104, a deuterated analog under development at low doses for depression

{{Reflist}}

{{Antipsychotics}}

{{Dopamine receptor modulators}}

{{Serotonin receptor modulators}}

Category:5-HT1A agonists

Category:Atypical antipsychotics

Category:Benzamides

Category:Chloroarenes

Category:D2 antagonists

Category:D3 antagonists

Category:D4 antagonists

Category:Phenol ethers

Category:Pyrrolidines