title: Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives.
abstract: Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the (35)S-GTP[γS] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. yzhang2@vcu.edu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Orgil
authors.initials: O
authors.lastname: Elbegdorj
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.forename: Irina O
authors.initials: IO
authors.lastname: Beletskaya
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
mesh_terms: D008968:Molecular Conformation; D009271:Naltrexone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009292:Narcotic Antagonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009292:Narcotic Antagonists; D009271:Naltrexone