6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand.

ABSTRACT: The 6β-N-heterocyclic naltrexamine derivative, NAP, has been demonstrated to be a peripherally selective mu opioid receptor modulator. To further improve peripheral selectivity of this highly potent ligand, its pyridal ring was quaterinized with benzyl bromide to produce BNAP. In radioligand binding assay, the Ki of BNAP for MOR was 0.76 ± 0.09 nM and was >900-fold more selective for MOR than DOR. The Ki for KOR was 3.46 ± 0.05 nM. In [(35)S]GTPγS ligand stimulated assay, BNAP showed low agonist efficacy with 14.6% of the maximum response of DAMGO with an EC50 of 4.84 ± 0.6 nM. However, unlike its parent compound NAP, BNAP displayed partial agonist activity at KOR with % maximum response at 45.9 ± 1.7% of U50,488H. BNAP did not reverse morphine-induced antinociception when administered sub

SUBMITTER: Williams DA 

PROVIDER: S-EPMC5125022 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature