AY-30191

The present isolated tissue study was designed to quantitate the alpha-adrenoceptor agonist activity of AY- 30,191 (5-(1-hydroxy-2-amino-ethyl)-1H-indole-7-carboxamide) and a series of related compounds. AY-30,191 induced contractions in the rabbit aorta, which were blocked by prazosin. In the rat vas deferens, while clonidine inhibited the electrically induced twitch response, AY-30,191 caused a prazosin-sensitive augmentation. In the dog saphenous vein, rauwolscine was less effective than the combination of rauwolscine and prazosin in inhibiting the contractions induced by AY-30,191. Pretreatment of the dog saphenous vein with phenoxybenzamine reduced the response to AY-30,191. The addition of rauwolscine to phenoxybenzamine-treated tissues had no effect on the contractions to AY-30,191 remaining after phenoxybenzamine treatment. These results suggest that AY-30,191 is a selective alpha 1-adrenoceptor agonist. Optimal alpha 1-adrenoceptor agonist activity in the 1H-indole-7-carboxamide series was seen in compounds in which a) the indole ring and the ethylamine side chain were intact; b) the indole nitrogen was unsubstituted; and c) the carboxamide was present at the 7-position in the indole ring. Removal of the carboxamide decreased alpha 1-adrenoceptor activity and, more importantly, resulted in a loss of alpha 1-adrenoceptor selectivity. Replacement of the carboxamide in the 7 position with methanesulfonamide resulted in a decrease in activity but a retention of alpha 1-adrenoceptor selectivity, whereas the dimethylamino analog was nonselective and the phosphoramidic acid diethylester analog was inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

The present isolated tissue study was designed to quantitate the α-adrenoceptor agonist activity of AY- 30,191 and a series of related compounds(I)(R= substituted aminoethyl, Et, HOCH₂, H₂NCH₂ or HON:CH; R¹=H or Me; R²=e.g.,H or CONH₂, 2,3-saturated or unsaturated).AY-30,191 induced contractions in the rabbit aorta, which were blocked by prazosin.In the rat vas deferens, while clonidine inhibited the elec. induced twitch response, AY-30,191 caused a prazosin-sensitive augmentation.In the dog saphenous vein, rauwolscine was less effective than the combination of rauwolscine and prazosin in inhibiting the contractions induced by AY-30,191.Pretreatment of the dog saphenous vein with phenoxybenzamine reduced the response to AY-30,191.The addition of rauwolscine to phenoxybenzamine-treated tissues had no effect on the contractions to AY-30,191 remaining after phenoxybenzamine treatment.Thus, AY-30,191 is a selective α₁-adrenoceptor agonist.Optimal α₁-adrenoceptor agonist activity in the 1H-indole-7-carboxamide series was seen in compounds in which a) the indole ring and the ethylamine side chain were intact; b) the indole N was unsubstituted; and c) the carboxamide was present at the 7-position in the indole ring.Removal of the carboxamide decreased α₁-adrenoceptor activity and, more importantly, resulted in a loss of α₁-adrenoceptor selectivity.Replacement of the carboxamide in the 7 position with methanesulfonamide resulted in a decrease in activity but a retention of α₁-adrenoceptor selectivity, whereas the dimethylamino analog was nonselective and the phosphoramidic acid diethylester analog was inactive.Thus, the 1H-indole-7-carboxamides are a novel series of selective α₁-adrenoceptor agonists and substitution at the 7 position determines α₁-adrenoceptor selectivity.