6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand.
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 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.
Department of Medicinal Chemistry, Virginia Commonwealth University , 800 E. Leigh Street, Richmond, Virginia 23298, United States.|Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
Dwight A
DA
Williams
Department of Medicinal Chemistry, Virginia Commonwealth University , 800 E. Leigh Street, Richmond, Virginia 23298, United States.
Yi
Y
Zheng
Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
Bethany G
BG
David
Department of Medicinal Chemistry, Virginia Commonwealth University , 800 E. Leigh Street, Richmond, Virginia 23298, United States.
Yunyun
Y
Yuan
Department of Medicinal Chemistry, Virginia Commonwealth University , 800 E. Leigh Street, Richmond, Virginia 23298, United States.
Saheem A
SA
Zaidi
Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
David L
DL
Stevens
Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
Krista L
KL
Scoggins
Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
Dana E
DE
Selley
Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
William L
WL
Dewey
Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, Richmond, Virginia 23298, United States.
Hamid I
HI
Akbarali
Department of Medicinal Chemistry, Virginia Commonwealth University , 800 E. Leigh Street, Richmond, Virginia 23298, United States.
Yan
Y
Zhang
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006168:Guinea Pigs; D007082:Ileum / Q000033:anatomy & histology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
C000624286:BNAP compound; D008024:Ligands; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone
Periphery selectivity; irritable bowel syndrome; mixed opioid ligand; opioid induced constipation; visceral pain