alpha 2-Adrenoceptor agonist properties of exo- and endo-isomers of 2-amino-6,7,dihydroxybenzonorbornene designed as rigid catecholamines.
A series of N-substituted exo- and endo-isomers of 2-amino-6,7-dihydroxybenzonorbornene, designed as rigid catecholamines, have been studied in the pithed rat in-vivo, as vasoconstrictor agents, and as inhibitors of the twitch response in the transmurally stimulated guinea-pig ileum. The exo-isomers examined were vasoconstrictor agonists in the pithed rat and inhibited the twitch response of the ileum. The corresponding endo-isomers were inactive in both preparations. The exo-isomers were less potent than the alpha 2-receptor agonist TL99, but were all directly acting vasoconstrictor agents, since they were still effective in reserpine-pretreated animals. Responses induced by members of the exo-series were selectively antagonized by the alpha 2-receptor antagonist rauwolscine, but were not antagonized by the alpha 1-receptor antagonist, prazosin, or the dopamine-receptor antagonist alpha-flupenthixol. The results demonstrate important conformational requirements for the interaction of catecholamines at presynaptic or postsynaptic alpha 2-receptors, and suggest that a fully extended or anti-conformation of the noradrenaline molecule is involved in alpha 2-receptor-agonist interaction.
D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis*; D000818:Animals; D002395:Catecholamines / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009636:Norbornanes / Q000138:chemical synthesis* / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000502:physiology; D013237:Stereoisomerism; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D002395:Catecholamines; D009636:Norbornanes; D015016:Yohimbine; C035439:2-amino-6,7-dihydroxybenzonorbornene; D011433:Propranolol; D011224:Prazosin