New 5-HT3 (Serotonin-3) Receptor Antagonists. IV. Synthesis and Structure-Activity Relationships of Azabicycloalkaneacetamide Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 43; no. 8; pp. 1351 - 1357
• Main Authors: KATO, Masayuki, ITO, Kiyotaka, NISHINO, Shigetaka, YAMAKUNI, Hisashi, TAKASUGI, Hisashi
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1995; Maruzen; Japan Science and Technology Agency
• Subjects: 2, 3-dihydro-1H-indole; 5-HT3 receptor antagonist; Acetamides - chemical synthesis; Acetamides - pharmacology; Alkanes - chemical synthesis; Alkanes - pharmacology; Animals; azabicycloalkaneacetamide; Biological and medical sciences; Blood Pressure - drug effects; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Heart Rate - drug effects; Magnetic Resonance Spectroscopy; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Reflex - drug effects; Serotonin Antagonists - chemical synthesis; Serotoninergic system; Structure-Activity Relationship; von Benzold-Jarisch reflex; Intravenous administration; Quinuclidine derivatives; Rat; Nitrogen heterocycle; Rodentia; Tropane derivatives; Vertebrata; Mammalia; Structure activity relation; Animal; Bicyclic compound; Carboxamide; Aromatic compound; Antagonist; Chemical synthesis; 5-HT3 receptor
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.43.1351

The synthesis and structure-activity relationships of a series of new azabicycloalkanes as 5-HT3 (serotonin-3) receptor antagonists are described. Our study on the azabicycloalkaneacetamide derivatives showed that 2, 3-dihydroindole as the aromatic ring moiety afforded potent 5-HT3 receptor antagonist activity, as judged by blockade of bradycardia induced by i.v. injection of 2-methylserotonin in anesthetized rats. 7-Azaindole as the aromatic moiety afforded weak 5-HT3 receptor antagonists activity. The best 5-HT3 antagonists in this study were endo-3, 3-diethyl- (9k) and 3, 3-dimethyl-2, 3-dihydro-1-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)acetyl-1H-indole (9d), being approximately 10-fold more potent than ondansetron (1). This study shows that the azabicycloalkaneacetyl group is a new pharmacophoric element as a basic nitrogen and a linking carbonyl moiety.