Medicinal Chemistry of Drugs Acting on Central and Peripheral Opioid Receptors

National Institute On Drug Abuse

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Abstract

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. [unreadable] [unreadable] 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. [unreadable] [unreadable] We reported a new chemical synthesis that eliminates the need for chromatographic separation in order to obtain multigram quantities of I (J-113397), a competitive antagonist of the nociceptin N/OFQ-NOP receptor system. N-benzyl protected 4-oxo-3-piperidinecarboxylate was used as the starting material to obtain an N-benzyl intermediate that could be resolved at a relatively early stage in the synthesis. The crucial step in the synthesis was the one-pot reduction of the double bond of a beta-enamino ester functionality by magnesium metal in methanol followed by epimerization to the desired trans-diastereoisomer intermediate. We prepared multiple decagrams of J-113397 and its enantiomer that now enable pharmacologic studies of the N/OFQ-NOP receptor system.