title: Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist.
abstract: YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, showed a high affinity for cloned human 5-HT(2C) receptors (K(i): 0.89 nM). The functional selectivity for 5-HT(2C) receptors in the 5-HT(2) receptor family was the highest among 5-HT(2C) receptor agonists, including m-chlorophenylpiperazine (mCPP) and Ro60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine). Oral administration of YM348 induced penile erections and hypolocomotion in rats, being completely inhibited by a selective 5-HT(2C) receptor antagonist, SB242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline). The dose-response curve for penile erections, unlike that for hypolocomotion, was an inverted U-shape in the dose range of 0.0677-2.03 mg/kg. A selective 5-HT(2A) receptor antagonist, MDL100907 (R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol), and a selective 5-HT(2B) receptor antagonist, RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine), had no effect on the decline in penile erection frequency at 2.03 mg/kg of YM348. YM348 did not affect blood pressure at 2.03 mg/kg. In conclusion, YM348 is a novel, potent and orally active 5-HT(2C) receptor agonist, and neither the activation of 5-HT(2A) or 5-HT(2B) receptors nor a cardiovascular effect is likely to contribute to the inverted U-shape dose-response curve for penile erections.
authors.affiliation: Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. kimura_y@yamanouchi.co.jp
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Kimura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hatanaka
authors.forename: Yuki
authors.initials: Y
authors.lastname: Naitou
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Maeno
authors.forename: Itsuro
authors.initials: I
authors.lastname: Shimada
authors.forename: Akiko
authors.initials: A
authors.lastname: Koakutsu
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Wanibuchi
authors.forename: Tokio
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D007191:Indazoles; D007211:Indoles; D010716:Phosphatidylinositols; D011743:Pyrimidines; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; C488691:YM348; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine