title: Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists.
abstract: Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible mu opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K(i) = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the delta receptor (DOR) and more than 150-fold selectivity over the kappa receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Aschenbach
authors.forename: Jianyang
authors.initials: J
authors.lastname: Chen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cassidy
authors.forename: David L
authors.initials: DL
authors.lastname: Stevens
authors.forename: Bichoy H
authors.initials: BH
authors.lastname: Gabra
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.forename: Richard B
authors.initials: RB
authors.lastname: Westkaemper
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009019:Morphinans / Q000138:chemical synthesis* / Q000494:pharmacology; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: C550365:17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-((3'-isoquinolyl)acetamido)morphinan; C550364:17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-((4'-pyridyl)acetamido)morphinan; D000700:Analgesics; D000701:Analgesics, Opioid; D008024:Ligands; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine