Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior Journal Article
| Authors: | Váradi, A.; Marrone, G. F.; Eans, S. O.; Ganno, M. L.; Subrath, J. J.; Le Rouzic, V.; Hunkele, A.; Pasternak, G. W.; McLaughlin, J. P.; Majumdar, S. |
| Article Title: | Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior |
| 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. © 2015 American Chemical Society. |
| Keywords: | opioid analgesics; delta; kappa; cocaine addiction; ibntxa; mp1104 |
| Journal Title: | ACS Chemical Neuroscience |
| Volume: | 6 |
| Issue: | 11 |
| ISSN: | 1948-7193 |
| Publisher: | American Chemical Society |
| Date Published: | 2015-11-18 |
| Start Page: | 1813 |
| End Page: | 1824 |
| Language: | English |
| DOI: | 10.1021/acschemneuro.5b00153 |
| PROVIDER: | scopus |
| PMCID: | PMC4651729 |
| PUBMED: | 26325040 |
| DOI/URL: | |
| Notes: | Export Date: 2 December 2015 -- Source: Scopus |
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