Substituted benzamides with conformationally restricted side chains. 5. Azabicyclo[x.y.z] derivatives as 5-HT4 receptor agonists and gastric motility stimulants

• Published in: Journal of medicinal chemistry 1993-03, Vol.36 (6), p.683-689
• Main Authors: King, Frank D, Hadley, Michael S, Joiner, Karen T, Martin, Roger T, Sanger, Gareth J, Smith, Duncan M, Smith, Gillian E, Smith, Paul, Turner, David H, Watts, Eric A
• Format: Article
• Language: English
• Subjects: Animals; Aza Compounds - chemical synthesis; Aza Compounds - pharmacology; Benzamides - chemical synthesis; Benzamides - pharmacology; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - pharmacology; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Gastrointestinal Motility - drug effects; Guinea Pigs; Male; Muscle Contraction - drug effects; Rats; Rats, Wistar; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00058a004

The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.