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

ACS Chemical Neuroscience
András VáradiSusruta Majumdar

Abstract

3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-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.

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Citations

Apr 13, 2018·Anesthesia and Analgesia·Valerie Le RouzicGavril W Pasternak
Dec 7, 2018·Neuropsychopharmacology Reports·Kazuki FujiiKeizo Takao
May 7, 2019·Frontiers in Pharmacology·Kendall L MoresRichard M van Rijn
Sep 12, 2020·The Journal of Pharmacology and Experimental Therapeutics·Kelly F PatonBronwyn M Kivell
Jan 1, 2021·Neuropharmacology·Diana Vivian AtigariBronwyn Maree Kivell
Sep 24, 2020·Current Topics in Medicinal Chemistry·Hirokazu Mizoguchi, Hideaki Fujii
Nov 17, 2021·Journal of Medicinal Chemistry·Soumen ChakrabortySusruta Majumdar
Nov 23, 2021·Frontiers in Pharmacology·Anna M GutridgeRichard M van Rijn

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