The orvinols and related opioids--high affinity ligands with diverse efficacy profiles

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.