ABSTRACT
Introduction: Morphine, the main active ingredient of opium, and other clinically useful opioid analgesics all mediate their effects by activating the mu opioid receptor (MOR). Studies involving MOR knockout mice have shown that the interaction with the MOR is also responsible for the many notorious side effects associated with these drugs including dependence and addiction [1]. Therefore, selective antagonists for the MOR are needed to study its function in drug abuse and addiction.Goal: Design and synthesis of a series of naltrexone derivatives and determination of their pharmacological profile at all three opioid receptors.Material and methods: Based on the lead compound that was previously identified in our lab, a series of 14-N-substituted naltrexone derivatives were synthesized. Thebaine was used as the starting material and the naltrexone derivatives were synthesized in multiple steps using various organic synthesis methods. The final compounds were purified using column chromatography and characterized using IR, NMR, mass spectroscopy, HPLC, and melting point. The final compounds were then tested in a competitive radioligand binding assay at the mu, kappa, and delta opioid receptors using [3H]naloxone, [3H]diprenorphine, and [3H]naltrindole to label the receptors respectively. The [35S]GTPγS binding assay was employed to determine the relative efficacy of these compounds at the MOR.Results: Competitive binding assay results showed that the naltrexone derivatives with amide linkageto various heterocyclic aromatic rings have a subnanomolar to nanomolar affinity for all three opioid receptors. The lead compound of the series was shown to be dually selective for the mu and kappa opioid receptors over the delta opioid receptor. Furthermore in the [35S]GTPγS binding functional assay, the lead compound was determined to be an antagonist at both mu and kappa opioid receptors.Conclusion: It is well established that MOR antagonists by themselves can be effective at treating various forms of drug addiction [2]. Furthermore, there is growing evidence that suggests KOR antagonists may be beneficial in lowering drug cravings and preventing relapse in addicts [3]. MOR-KOR dual-antagonists may find novel clinical utility as therapeutic agents in the treatment of opioid dependence.References:1. Matthes H. “Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene” Nature [383], 1996.2. Garbutt, J. “Efficacy and tolerability of naltrexone in the management of alcohol dependence” Current Pharmaceutical Design [16], 2010.3. Redila, V. “Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system” Psychopharmacology [200], 2008.