We have continued our studies of the opioid receptor-endorphin system from medicinal chemical and pharmacological directions. This system consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types and their subtypes located in anatomically well defined areas of the mammalian CNS with the numerous endogenous opioid peptides (endorphins) which subserve these receptors. These results present many opportunities for research highly relevant to drug abuse and for the development of new medications that act on these receptors. The opioid receptor endorphin system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state including regulation of dopamine (DA) levels in the nucleus accumbens (NAC) and expression of the effects of alcohol and cocaine. This system is dysregulated by the abuse of heroin and prescription narcotics resulting in tolerance and dependence. Recent pharmacologic advances have shown that moderately selective delta opioid antagonists suppress (a) cocaine seeking behavior, (b) heroin self-administration and (c) the development of tolerance and dependence to the mu agonist morphine. The former two observations strongly indicate that highly selective delta receptor antagonists might be valuable medications for the treatment and prevention of human cocaine and narcotic abuse and perhaps other undesirable reinforcing behaviors. The latter observation suggests that a drug showing a mu agonist-delta antagonist profile might produce strong analgesia without producing tolerance and dependence thus allowing continuous treatment of chronic pain. The exploitation of these and other similarly intriguing observations now requires novel, exquisitely selective, nonpeptide ligands as research tools and potential medications. These new tools will enable the study of many questions of fundamental importance concerning the function of mu, delta and kappa opioid receptor subtypes and how drugs interact with their receptors to elicit these functions. We have continued to design, synthesize and evaluate novel drugs for this purpose during the reporting period. The 5-phenylmorphans are a particularly interesting class of opioid receptor agonists that were originated by Everette May at NIH in 1955. We earlier identified a mu agonist-delta antagonist and a delta inverse agonist in this series. We have now identified a morphine-like mu agonist and also a mu antagonist in a series of conformationally restrained 5-phenylmorphans. The diverse profiles obtained in this series illustrate the importance of subtle changes on the carbon-nitrogen skeleton and careful attention to stereochemical detail and provide important leads toward novel pain medications with reduced side effects and further understanding of drug-receptor interactions. We recently completed the chemical synthesis and in vitro opioid receptor binding and functional studies of the final pair of 12 racemic topologically rigid N-methyl and N-phenethyl analogues of oxide-bridged 5-phenylmorphans, the ortho- and para-b-isomers. These compounds were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction present in the ring system. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. Once activated, the fluorine served as the leaving group for closure of the final ring, the oxide bridge. The ortho and para-b-N-phenethyl isomers were moderately potent delta and kappa opioid receptor antagonists. These results provide further insight into structural requirements for narcotic antagonist activity in this series.
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