title: Characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives as novel leads to development of mu opioid receptor selective antagonists.
abstract: As important pharmacological probes, highly selective opioid receptor antagonists are essential in opioid receptor structural characterization and opioid agonist functional studies. At present, a nonpeptidyl, highly selective, and reversible mu opioid receptor antagonist is still not available. Among a series of novel naltrexamine derivatives that have been designed and synthesized following molecular modeling studies, two compounds, NAP and NAQ, were identified as leads based on the results of in vitro and in vivo pharmacological assays. Both of them displayed high binding affinity and selectivity to the mu opioid receptor. Further pharmacokinetic and functional characterization revealed that NAP seems to be a peripheral nervous system agent while NAQ seems to be a central one. Such characteristics provide two distinguished potential application routes for these two agents and their derivatives. These results also supported our hypothesis that they may serve as leads to develop more potent and selective antagonists for the mu opioid receptor.
authors: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, Virginia 23298, USA.
authors: Yunyun
authors: Y
authors: Yuan
authors: Guo
authors: G
authors: Li
authors: Hengjun
authors: H
authors: He
authors: David L
authors: DL
authors: Stevens
authors: Patrick
authors: P
authors: Kozak
authors: Krista L
authors: KL
authors: Scoggins
authors: Pallabi
authors: P
authors: Mitra
authors: Phillip M
authors: PM
authors: Gerk
authors: Dana E
authors: DE
authors: Selley
authors: William L
authors: WL
authors: Dewey
authors: Yan
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D016466:CHO Cells; D018938:Caco-2 Cells; D006224:Cricetinae; D003412:Cricetulus; D004343:Drug Implants; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000008:administration & dosage; D009021:Morphine Dependence / Q000523:psychology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism
chemical_list: D004343:Drug Implants; D006571:Heterocyclic Compounds; D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; C035438:beta-naltrexamine; D009020:Morphine