Details

Autor(en) / Beteiligte

• Sawutz, D G
• Salvino, J M
• Dolle, R E
• Seoane, P R
• Farmer, S G

Titel

Pharmacology and structure--activity relationships of the nonpeptide bradykinin receptor antagonist WIN 64338

Ist Teil von

• Canadian journal of physiology and pharmacology, 1995-07, Vol.73 (7), p.805-811

Ort / Verlag

Canada

Erscheinungsjahr

1995

Quelle

MEDLINE

Beschreibungen/Notizen

• A series of competitive, nonpeptide bradykinin receptor antagonists based on an alpha-amino acid scaffold have been developed and biologically characterized. The lead compound in the series, WIN 64338, demonstrates competitive inhibition of bradykinin-mediated functional responses through B2 receptors in a variety of tissues and species. WIN64338 is a specific for the bradykinin B2 receptor; it is inactive at both the B1 and B2 kinin receptors. In conscious guinea pigs, WIN 64338 inhibits kinin-mediated bronchoconstriction but does not attenuate a similar response to acetylcholine. A series of WIN 64338 analogues display a well-defined structure-activity relationship, strongly suggesting binding in a specific manner to the B2 receptor. Structure-activity data suggest that a hydrophobic binding pocket that prefers large aromatic groups in a specific conformational orientation exists in the receptor ligand binding domain. This class of nonpeptide bradykinin receptor antagonists may lead to the design of other compounds with enhanced receptor affinity and optimal in vivo biological activity.