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.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Váradi A,Marrone GF,Eans SO,Ganno ML,Subrath JJ,Le Rouzic V,Hunkele A,Pasternak GW,McLaughlin JP,Majumdar Sdoi
10.1021/acschemneuro.5b00153subject
Has Abstractpub_date
2015-11-18 00:00:00pages
1813-24issue
11issn
1948-7193journal_volume
6pub_type
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