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

A. Váradi, 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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1813-1824
Number of pages12
JournalACS Chemical Neuroscience
Volume6
Issue number11
DOIs
Publication statusPublished - Sep 1 2015

Fingerprint

kappa Opioid Receptor
delta Opioid Receptor
Reward
Cocaine
Lead compounds
Analgesics
Assays
Cocaine-Related Disorders
Opioid Receptors
Scaffolds
Morphine
Opioid Analgesics
Chemical activation
Pharmacology
Derivatives
Lead

Keywords

  • cocaine addiction
  • delta
  • IBNtxA
  • kappa
  • MP1104
  • Opioid analgesics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior. / Váradi, A.; Marrone, Gina F.; Eans, Shainnel O.; Ganno, Michelle L.; Subrath, Joan J.; Le Rouzic, Valerie; Hunkele, Amanda; Pasternak, Gavril W.; McLaughlin, Jay P.; Majumdar, Susruta.

In: ACS Chemical Neuroscience, Vol. 6, No. 11, 01.09.2015, p. 1813-1824.

Research output: Contribution to journalArticle

Váradi, A, Marrone, GF, Eans, SO, Ganno, ML, Subrath, JJ, Le Rouzic, V, Hunkele, A, Pasternak, GW, McLaughlin, JP & Majumdar, S 2015, 'Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior', ACS Chemical Neuroscience, vol. 6, no. 11, pp. 1813-1824. https://doi.org/10.1021/acschemneuro.5b00153
Váradi, A. ; Marrone, Gina F. ; Eans, Shainnel O. ; Ganno, Michelle L. ; Subrath, Joan J. ; Le Rouzic, Valerie ; Hunkele, Amanda ; Pasternak, Gavril W. ; McLaughlin, Jay P. ; Majumdar, Susruta. / Synthesis and Characterization of a Dual Kappa-Delta Opioid Receptor Agonist Analgesic Blocking Cocaine Reward Behavior. In: ACS Chemical Neuroscience. 2015 ; Vol. 6, No. 11. pp. 1813-1824.
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