PHARMACOLOGY AND STRUCTURE ACTIVITY RELATIONSHIPS OF THE NONPEPTIDE BRADYKININ RECEPTOR ANTAGONIST WIN-64338

A series of competitive, nonpeptide bradykinin receptor antagonists ba sed on an alpha-amino acid scaffold have been developed and biological ly characterized. The lead compound in the series, WIN 64338, demonstr ates competitive inhibition of bradykinin-mediated functional response s through B-2 receptors in a variety of tissues and species. WIN 64338 is specific for the bradykinin B-2 receptor; it is inactive at both t he B-1 and B-3 kinin receptors. In conscious guinea pigs, WIN 64338 in hibits kinin-mediated bronchoconstriction but does not attenuate a sim ilar response to acetylcholine. A series of WIN 64338 analogues displa y a well-defined structure-activity relationship, strongly suggesting binding in a specific manner to the B-2 receptor. Structure-activity d ata suggest that a hydrophobic binding pocket that prefers large aroma tic groups in a specific conformational orientation exists in the rece ptor ligand binding domain. This class of nonpeptide bradykinin recept or antagonists may lead to the design of other compounds with enhanced receptor affinity and optimal in vivo biological activity.