Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior

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• 作者：Andr谩s V谩radi ; Gina F. Marrone ; Shainnel O. Eans ; Michelle L. Ganno ; Joan J. Subrath ; Valerie Le Rouzic ; Amanda Hunkele ; Gavril W. Pasternak ; Jay P. McLaughlin ; Susruta Majumdar
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：November 18, 2015
• 年：2015
• 卷：6
• 期：11
• 页码：1813-1824
• 全文大小：520K
• ISSN：1948-7193

文摘

3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6尾-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED₅₀ = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED₅₀. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.