Hieble J P, Sulpizio A C, Nichols A J, DeMarinis R M, Pfeiffer F R, Lavanchy P G, Ruffolo R R
J Hypertens Suppl. 1986 Dec;4(6):S189-92.
It is now recognized that two post-junctional alpha-adrenoceptors mediate vascular constriction. The vascular alpha 2-adrenoceptors seem to be particularly sensitive to circulating catecholamine levels, in contrast to the alpha 1-adrenoceptors, which are activated primarily by neuronally released norepinephrine. Most alpha 2-adrenoceptor antagonists do not discriminate between the pre-junctional neuroinhibitory alpha 2-adrenoceptor and the post-junctional vascular alpha 2-adrenoceptor. However, we have synthesized and characterized a compound (SK&F 104078: 6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine) which is a potent antagonist at post-junctional vascular alpha 2-adrenoceptors in vitro but has no effect at pre-junctional neuroinhibitory alpha 2-adrenoceptors. The post-junctional selectivity of SK&F 104078 has been confirmed by in vivo studies determining pre- and post-junctional alpha 2-adrenoceptor antagonist activity in the pithed rat. The ability to selectively block post-junctional alpha 2-adrenoceptors offers a novel approach to antihypertensive therapy, since the vasoconstrictor effects of circulating catecholamines can be attenuated without influencing the feedback control of transmitter release operating via pre-junctional alpha 2-adrenoceptors, and excess sympathoadrenal tone can be reduced without affecting normal neurovascular transmission.
现在已经认识到，两种节后α-肾上腺素能受体介导血管收缩。与主要由神经元释放的去甲肾上腺素激活的α1-肾上腺素能受体相比，血管α2-肾上腺素能受体似乎对循环中的儿茶酚胺水平特别敏感。大多数α2-肾上腺素能受体拮抗剂不能区分节前神经抑制性α2-肾上腺素能受体和节后血管α2-肾上腺素能受体。然而，我们已经合成并表征了一种化合物（SK&F 104078：6-氯-9-[(3-甲基-2-丁烯基)氧基]-3-甲基-2,3,4,5-四氢-1H-3-苯并氮杂卓），它在体外是节后血管α2-肾上腺素能受体的强效拮抗剂，但对节前神经抑制性α2-肾上腺素能受体没有作用。SK&F 104078的节后选择性已通过在去大脑大鼠中测定节前和节后α2-肾上腺素能受体拮抗剂活性的体内研究得到证实。选择性阻断节后α2-肾上腺素能受体的能力为抗高血压治疗提供了一种新方法，因为循环中的儿茶酚胺的血管收缩作用可以减弱，而不会影响通过节前α2-肾上腺素能受体进行的递质释放的反馈控制，并且可以在不影响正常神经血管传递的情况下降低过多的交感肾上腺张力。
