In vitro characterization of the adrenoceptor activity of AY-28,925

TJ Rimele, RJ Heaslip, DK Lee and D Grimes

The adrenoceptor activity of AY-28,925 (5-[1-hydroxy-2-[(1-methyl-3- phenylpropyl)amino]ethyl]-1 H-indole-7-carboxamide) was evaluated on various isolated vascular and nonvascular tissues. Based upon pA2 values derived from either the antagonism of the effect of isoproterenol on paced guinea pig left atria (pA2 = 7.3), spontaneously beating guinea pig right atria (pA2 = 7.4) or canine saphenous vein (pA2 = 7.3), AY-28,925 demonstrated nonselective beta adrenoceptor antagonist activity. Studies using the spontaneously beating guinea pig right atria and the prostaglandin F2 alpha-contracted canine saphenous vein indicated that AY-28,925 also possessed nonselective beta- adrenoceptor intrinsic efficacy. AY-28,925 was shown to be a selective alpha-1 adrenoceptor antagonist with a pA2 value which was greater against phenylephrine in the rabbit aorta (pA2 = 6.6) than against clonidine in the rat vas deferens (pA2 = 5.4) or B-HT 920 in the canine saphenous vein (pA2 = 5.3). Only in concentrations greater than 2000 times those required for adrenergic activity was AY-28,925 able to inhibit potassium chloride- or prostaglandin F2 alpha-induced contractions of the rabbit aorta. The compound had no significant negative intropic activity. These experiments indicate that AY-28,925 possesses, in decreasing orders of activity: nonselective beta- adrenoceptor properties; a selective alpha-1 adrenoceptor inhibitory effect; and a nonspecific direct relaxing action on vascular smooth muscle.

Volume 239, Issue 1, pp. 1-8, 10/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics