Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior
| Autor: | Jay P. McLaughlin, András Váradi, Gavril W. Pasternak, Michelle L. Ganno, Shainnel O. Eans, Valerie Le Rouzic, Gina F. Marrone, Susruta Majumdar, Amanda Hunkele, Joan J. Subrath |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Nociception Agonist Physiology medicine.drug_class Cognitive Neuroscience Analgesic Drug Evaluation Preclinical Receptors Opioid mu Spatial Behavior Pharmacology Biochemistry Article IBNtxA δ-opioid receptor Cocaine-Related Disorders Random Allocation Cocaine Dopamine Uptake Inhibitors Reward Receptors Opioid delta Conditioning Psychological medicine Animals Receptor Mice Knockout Molecular Structure Chemistry Receptors Opioid kappa Nuclear Receptor Subfamily 1 Group F Member 1 Cell Biology General Medicine Naltrexone Conditioned place preference Analgesics Opioid Mice Inbred C57BL Morphinans Opioid Morphine medicine.drug |
| Zdroj: | ACS Chemical Neuroscience. 6:1813-1824 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.5b00153 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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