Salvinorin A analogs as probes in opioid pharmacology

The body of knowledge of the chemistry, pharmacology, and neurobiology of opioid receptors continues to grow rapidly. Despite these advances, many aspects of the three-dimensional structure of μ, δ, and κ opioid receptors remain elusive. Salvia divinorum and its major active component 2a have the potential to identify novel opioid receptor probes that will aid in addressing these aspects, as well as opening additional areas for chemical investigation. Opioid agonists based on 2a have the potential to treat pain, cough, diarrhea, stimulant dependence, and mood disorders. Antagonists derived from 2a have potential utility in treating a number of conditions including drug dependence, depression, opioid-induced constipation, and obesity. Thus, analogues of 2a may prove to be excellent research tools and give greater insight into opioid receptor mediated phenomena. Medicinal chemistry efforts have begun to explore the structure-activity relationship studies of 2a. To date, these have mainly focused on its high affinity and selectivity for the KOP. Future work is likely to identify additional analogues of 2a with altered selectivity for MOPs and DOPs, as well as novel allosteric modulators of opioid receptors. The SAR known at this time is summarized in Figure 13. At the C-1 position, (1) reduction or removal of the carbonyl is tolerated, and (2) introduction of a 1,10-alkene increases the likelihood of antagonist activity. At the C-2 position, (1) small alkyl esters favor binding to KOPs, whereas aromatic esters favor binding to MOPs, (2) replacement of the acetoxy with ethers and amines is tolerated, (3) generally α-substituents are preferred over the corresponding α-substituents, and (4) bioisosteric replacement of the acetoxy group with amide, thioester, and sulforate esters is tolerated. At the C-4 position, (1) small alkyl chains are preferential for binding to KOPs, (2) hydrolysis or reduction of the carbomethoxy group leads to reduced affinity at KOPs, and (3) generally conversion to an amide is not tolerated. At the C-17 position, (1) reduction or removal of the carbonyl is tolerated, and (2) introduction of an 8,17-alkene is also tolerated. Finally at C-12, the furan ring may be reduced or replaced, but this leads to a reduction in affinity. Several models suggest that the affinity and selectivity of 2a for KOPs is the result of interactions with unique residues compared with other KOP ligands. In 1929, the eminent pharmacologist Reid Hunt articulated a guiding premise for the development of a program at the NIH to address drug abuse problems. He stated that, "A thorough study of the morphine molecule might show a possibility of separating the analgesic from the habit forming property ... work along these lines would involve cooperation between the highest type of organic chemists and pharmacologists." Studies under this directive lead to the identification of metopon (6). Early preliminary pharmacological studies of 6 in animals and humans showed this compound to retain morphine-like analgesia but cause fewer undesirable side effects than morphine. These observations provided the initial "proof of principle" that permeates contemporary opioid research. Continued research into chemistry and pharmacology of opioid receptor ligands, such as 2a or other natural products, may yet yield the holy grail of opioids.