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

The 6 beta-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 K-i of BNAP for MOR was 0.76 +/- 0.09 nM and was >900-fold more selective for MOR than DOR The K-i for KOR was 3.46 +/- 0.05 nM. In [S-35]GTP gamma S 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 subcutaneously but did antagonize when administered intracerebroventricularly. BNAP antagonized morphine-induced contractions of the circular muscle in mice colon. BNAP inhibition of field-stimulated contractions in longitudinal muscle strips for the guinea-pig ileum were also blocked by nor-BNI, a kappa opioid receptor antagonist. BNAP induced inhibition of acetic acid induced abdominal stretching in chronic morphine treated mice. These findings suggest that BNAP is a dual MOR antagonist/KOR agonist and may have functional use in irritable bowel patients.