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6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand
journal contribution
posted on 2016-06-06, 00:00 authored by Dwight A. Williams, Yi Zheng, Bethany
G. David, Yunyun Yuan, Saheem A. Zaidi, David L. Stevens, Krista L. Scoggins, Dana E. Selley, William L. Dewey, Hamid I. Akbarali, Yan ZhangThe
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 [35S]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
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.