Conformational requirements for histamine H sub(2)-receptor inhibitors: A structure-activity study of phenylene analogues related to cimetidine and tiotidine

Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H sub(2) receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene u...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1983-01, Vol.26 (2), p.140-144
Main Authors: Hoffman, J M, Pietruszkiewicz, AM, Habecker, C N, Phillips, B T, Bolhofer, WA, Cragoe, EJ Jr, Torchiana, M L, Lumma, WC Jr, Baldwin, J J
Format: Article
Language:English
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Summary:Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H sub(2) receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene unit. These compounds were evaluated for antagonism of the dimaprit-stimulated chronotropic response in the guinea pig atrium and inhibition of histamine stimulated secretion of gastric acid in the dog. In both series, biological activity is markedly dependent on the m-phenylene regioisomers. Histamine H sub(2)-receptor activity is retained in both series; however, in the tiotidine series, gastric antisecretory activity is significantly improved. The electronic influences of the phenylene unit on biological activity were also evaluated. Itwas concluded that the geometric constraints imposed by the m-phenylene connecting element were more important than electronic factors in binding events at the histamine H sub(2) receptor.
ISSN:0022-2623