Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist

• Published in: European journal of pharmacology Vol. 483; no. 1; pp. 37 - 43
• Main Authors: Kimura, Yasuharu, Hatanaka, Ken-ichi, Naitou, Yuki, Maeno, Kyoichi, Shimada, Itsuro, Koakutsu, Akiko, Wanibuchi, Fumikazu, Yamaguchi, Tokio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.01.2004; Elsevier
• Subjects: 5-HT (5-hydroxytryptamine, serotonin); 5-HT2C receptor; Aminopyridines - pharmacology; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Cell Membrane - drug effects; Cell Membrane - metabolism; CHO Cells; Cloning, Molecular; Cricetinae; Depression, Chemical; Dose-Response Relationship, Drug; Hemodynamics - drug effects; Hypolocomotion; Indazoles - pharmacology; Indoles - pharmacology; Male; mCPP (m-chlorophenylpiperazine); MDL100907; Medical sciences; Motor Activity - drug effects; Penile erection; Penile Erection - drug effects; Pharmacology. Drug treatments; Phosphatidylinositols - metabolism; Pyrimidines - pharmacology; Rats; Ro60-0175; RS-127445; SB242084; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists - pharmacology; Synaptic Transmission - drug effects; Ro60-0175; MDL100907; 5-HT (5-hydroxytryptamine, serotonin); Hypolocomotion; RS-127445; Penile erection; SB242084; mCPP (m-chlorophenylpiperazine); 5-HT2C receptor; Agonist; serotonin); 5-HT2C receptor; Penile erection; Hypolocomotion; mCPP (m-chlorophenylpiperazine); Ro60-0175; SB242084; MDL100907; RS-127445; Serotonin; Erection; Oral administration; Neurotransmitter; 5-HT2C serotonin receptor; 5-HT (5-hydroxytryptamine
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2003.10.004

YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, showed a high affinity for cloned human 5-HT2C receptors (Ki: 0.89 nM). The functional selectivity for 5-HT2C receptors in the 5-HT2 receptor family was the highest among 5-HT2C 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-HT2C 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-HT2A receptor antagonist, MDL100907 (R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol), and a selective 5-HT2B 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-HT2C receptor agonist, and neither the activation of 5-HT2A or 5-HT2B receptors nor a cardiovascular effect is likely to contribute to the inverted U-shape dose–response curve for penile erections.