A-315456:: a selective α1D-adrenoceptor antagonist with minimal dopamine D2 and 5-HT1A receptor affinity

In functional assays, A-315456, N-[3-(cyclohexylidene-(1H-imidazol-4-ylmethyl))phenyl]ethanesulfonamide, behaved as an alpha (1D)-adrenoceptor subtype selective antagonist (pA(2) = 8.34) in the rat aorta. It was 83-fold less potent at the alpha (1B)-adrenoceptor subtype expressed in the rat spleen, and was inactive at the alpha (1A)-adrenoceptor subtype expressed in the rat vas deferens. Radioligand binding assays also revealed high affinity (pK(i) = 8.71) for the alpha (1D)-adrenoceptor subtype and weaker affinities at the alpha (1A)-adrenoceptor (pK(i) = 6.23) and alpha (1B)-adrenoceptor (pK(i) = 7.86). In comparison to its potent affinity at the alpha (1D)-adrenoceptor subtype, A-315456 was 3020-, 794- and 38-fold weaker at the dopamine D-2-, 5-HT1A-, and alpha (2a)-adrenoceptors, respectively. These studies indicate that A-315456 is a potent and selective alpha (1D)-antagonist that may serve as a useful pharmacological ligand to probe the physiological role of the alpha (1D)-adrenoceptor subtype in normal and disease states. (C) 2001 Elsevier Science B.V. All rights reserved.