title: Structure-activity relationships of 1H-indole-7-carboxamides as a novel series of selective alpha 1-adrenoceptor agonists.
abstract: 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)
authors.affiliation: Department of Experimental Therapeutics, Wyeth-Ayerst Research, Princeton, NJ.
authors.forename: T J
authors.initials: TJ
authors.lastname: Rimele
authors.forename: T J
authors.initials: TJ
authors.lastname: Caggiano
authors.forename: S K
authors.initials: SK
authors.lastname: Buckley
authors.forename: W J
authors.initials: WJ
authors.lastname: Dustman
authors.forename: J
authors.initials: J
authors.lastname: Schmid
authors.forename: R J
authors.initials: RJ
authors.lastname: Heaslip
authors.forename: D
authors.initials: D
authors.lastname: Grimes
authors.forename: A A
authors.initials: AA
authors.lastname: Asselin
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D004285:Dogs; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D012501:Saphenous Vein / Q000187:drug effects; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D000316:Adrenergic alpha-Agonists; D007211:Indoles; C059746:5-(1-hydroxy-2-aminoethyl)-1H-indole-7-carboxamide