2. Academic Validation
  3. Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor

Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor

  • Eur J Med Chem. 2014 Oct 6:85:818-29. doi: 10.1016/j.ejmech.2014.07.077.
Prabhakar R Polepally 1,  Krzysztof Huben 2,  Eyal Vardy 3,  Vincent Setola 3,  Philip D Mosier 4,  Bryan L Roth 3,  Jordan K Zjawiony 5
Affiliations

Affiliations

  • 1 Department of BioMolecular Sciences, Division of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
  • 2 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.
  • 3 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.
  • 4 Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
  • 5 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: [email protected].
PMID: 25193297 DOI: 10.1016/j.ejmech.2014.07.077
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.

Keywords

Kappa, delta, and mu opioid receptors; Michael acceptor-type ligands; Molecular modeling; Salvinorin A and B.

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