Hicks P E, Waldron C, Burn P, Crooks P A
J Pharm Pharmacol. 1983 Feb;35(2):94-9. doi: 10.1111/j.2042-7158.1983.tb04276.x.
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.
一系列被设计为刚性儿茶酚胺的2-氨基-6,7-二羟基苯并降冰片烯的N-取代外型和内型异构体，已在麻醉大鼠体内作为血管收缩剂以及作为跨膜刺激豚鼠回肠抽搐反应的抑制剂进行了研究。所检测的外型异构体在麻醉大鼠中是血管收缩激动剂，并能抑制回肠的抽搐反应。相应的内型异构体在两种制剂中均无活性。外型异构体的效力低于α2受体激动剂TL99，但都是直接作用的血管收缩剂，因为它们在利血平预处理的动物中仍然有效。外型系列成员诱导的反应被α2受体拮抗剂萝芙素选择性拮抗，但不被α1受体拮抗剂哌唑嗪或多巴胺受体拮抗剂α-氟哌噻吨拮抗。结果表明儿茶酚胺在前突触或后突触α2受体相互作用中存在重要的构象要求，并表明去甲肾上腺素分子的完全伸展或反式构象参与α2受体激动剂相互作用。
