α2-Adrenoceptor agonist properties of exo- and endo-isomers of 2-amino-6,7,dihydroxybenzo-norbornene designed as rigid catecholamines

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Abstract
A series of N-substituted exo- and endo-isomers of 2-amino-6,7-dihydroxybenzo-norbornene, 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 α2-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 antanonized by the α2-receptor antagonist rauwolscine, but were not antagonized by the α1-receptor antagonist, prazosin, or the dopamine-receptor antagonist α-flupenthixol. The results demonstrate important conformational requirements for the interaction of catecholamines at presynaptic or postsynaptic α2-receptors, and suggest that a fully extended or anti-conformation of the noradrenaline molecule is involved in α2-receptor-agonist interaction.