title: Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor.
abstract: The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand-receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure-activity relationships, and previous salvinorin A-KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.
authors.affiliation: Department of BioMolecular Sciences, Division of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
authors.forename: Prabhakar R
authors.initials: PR
authors.lastname: Polepally
authors.affiliation: Department of BioMolecular Sciences, Division of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA; Institute of Organic Chemistry, Technical University of Lodz, 90-924 Lodz, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Huben
authors.affiliation: Department of Pharmacology, Division of Chemical Biology and Medicinal Chemistry, Medical School, NIMH Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.affiliation: Department of Pharmacology, Division of Chemical Biology and Medicinal Chemistry, Medical School, NIMH Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Setola
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.affiliation: Department of Pharmacology, Division of Chemical Biology and Medicinal Chemistry, Medical School, NIMH Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of BioMolecular Sciences, Division of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA. Electronic address: jordan@olemiss.edu.
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
mesh_terms: D045785:Diterpenes, Clerodane / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017473:Receptors, Opioid, kappa / Q000737:chemistry / Q000378:metabolism*
chemical_list: D045785:Diterpenes, Clerodane; D008024:Ligands; D017473:Receptors, Opioid, kappa; C090499:salvinorin A
keywords: Kappa, delta, and mu opioid receptors; Michael acceptor-type ligands; Molecular modeling; Salvinorin A and B