Lewis John W, Husbands Stephen M
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Curr Pharm Des. 2004;10(7):717-32. doi: 10.2174/1381612043453027.
The thevinols and orvinols derived from thebaine via the thebaine-methylvinyl ketone adduct (thevinone) were thoroughly investigated in the 1960's and 1970's by the Reckitt group. From this work a number of important opioids emerged. Buprenorphine is a mu partial agonist, kappa/delta-antagonist that is now used primarily in the treatment of heroin abuse and dependence though it was initially launched as an analgesic for the treatment of moderate to severe pain. Etorphine and dihydroetorphine are very potent mu agonists that have found application in veterinary and human medicine respectively. Diprenorphine is primarily a mu antagonist though it also has some kappa-partial agonist effects. It has high affinity for all types of opioid receptors and as a "universal" opioid ligand has been much in demand as a pharmacological tool. It has also been converted into a [11C] version for use in Positron Emission Tomography (PET) studies of brain function related to the opioid receptor system. More recent medicinal chemistry investigations have been concerned with gaining a greater understanding of buprenorphine's unique opioid profile. This has involved the synthesis and evaluation of a number of series of buprenorphine analogues in which the C20 t-butyl group has been constrained in a ring system. These studies have suggested that the methyls in the t-butyl group inhibit the conformational changes in the kappa-receptor required for generation of an agonist response. Introduction of a 7alpha-cinnamoylaminomethyl group in place of the orvinol tertiary alcohol function leads to selective irreversible mu antagonism.
20世纪60年代和70年代，瑞奇集团对通过蒂巴因-甲基乙烯基酮加合物（蒂巴酮）衍生而来的蒂巴诺尔和奥蒂诺尔进行了深入研究。从这项工作中涌现出了许多重要的阿片类药物。丁丙诺啡是一种μ部分激动剂、κ/δ拮抗剂，尽管它最初作为一种用于治疗中度至重度疼痛的镇痛药推出，但现在主要用于治疗海洛因滥用和成瘾。埃托啡和二氢埃托啡分别是非常强效的μ激动剂，已分别应用于兽医学和人类医学。二丙诺啡主要是一种μ拮抗剂，不过它也有一些κ部分激动剂的作用。它对所有类型的阿片受体都有高亲和力，作为一种“通用”的阿片类配体，作为一种药理学工具一直有很大需求。它也已被转化为[11C]版本，用于与阿片受体系统相关的脑功能正电子发射断层扫描（PET）研究。最近的药物化学研究关注于更深入地了解丁丙诺啡独特的阿片类特性。这涉及到一系列丁丙诺啡类似物的合成和评估，其中C20叔丁基被限制在一个环系统中。这些研究表明，叔丁基中的甲基抑制了κ受体产生激动剂反应所需的构象变化。用7α-肉桂酰氨基甲基取代奥蒂诺尔叔醇官能团会导致选择性不可逆的μ拮抗作用。
