DESIGN, SYNTHESES, AND BIOLOGICAL EVALUATION OF 14-N-SUBSTITUTED NALTREXONE DERIVATIVES AS OPIOID RECEPTOR LIGANDS

Opium, the dried resin obtained from the unripe seedpods of the poppy flower, has been used for medicinal and euphoric purposes since ancient times. Morphine, the main active ingredient of opium, and other clinically useful opioid analgesics all mediate their effects through activating the mu opioid receptor. Studies involving the mu opioid receptor knockout mice showed that the interaction with the mu opioid receptor is also responsible for many notorious side effects associated with these drugs including dependence and addiction. Therefore, selective antagonists for the mu opioid receptor are needed to study its function in drug abuse and addiction. Previously, based on molecular modeling studies and the “message-address” concept, a series of 14-O-substituted naltrexone derivatives were designed and synthesized. These compounds carried an ester-linked heteroaromatic substitution at the 14-position of naltrexone which was designed to interact with the putative “address” site, that was identified in the mu opioid receptor through molecular modeling studies. The lead compound of this series was determined to have a high affinity and selectivity for the mu opioid receptor. Because the 14-O-substituted naltrexone derivatives were not very stable, the ester linkage in these compounds was replaced by an amide one and a series of 14-N-substituted naltrexone derivatives were synthesized. The affinity and selectivity of these novel naltrexone derivatives were determined in a competitive radioligand binding assay. Interestingly, the 14-N-substituted naltrexone derivatives did not maintain the high selectivity of the 14-O-substituted series. It was hypothesized that the conformational constraint introduced by the amide linker was detrimental to the mu opioid receptor selectivity. Therefore, three 14-N-substituted naltrexone derivatives which carried more flexible linkages were synthesized and evaluated. The mu opioid receptor selectivity was not recovered by introducing rotational freedom into the linker. Some of these 14-N-substitued naltrexone derivatives were determined to be mu-kappa opioid receptor dual selective antagonists. Since the mu opioid receptor antagonists are effective at treating drug addiction, while growing evidence suggests that the kappa opioid receptor antagonists may be beneficial in lowering drug cravings, these novel mu-kappa opioid receptor dual selective antagonists may find unique clinical utility in the treatment of opioid dependence