New Michael Acceptor-type of Salvinorin A Ligands to Kappa-Opioid Receptor
Salvia divinorum (Lamiaceae) has drawn much attention in recent years due to its psychopharmacological properties. The active ingredient salvinorin A, is a potent κ-opioid receptor (KOR) agonist . Since its discovery, numerous synthetic analogues of salvinorin A have been reported at KOR, µ-opioid receptor (MOR) and δ-opioid receptor (DOR) . The current objective is to use the knowledge about salvinorin A-KOR interactions to rationally design salvinorin A derivatives with different pharmacological profiles and therapeutic potential. Previous work on the KOR model and analysis of the mode of binding of RB-64 (22-thiocyanatosalvinorin A) suggest that Cys-315 may be a good anchoring amino acid at the binding site in KOR . Considering the fact that Michael acceptors may strongly bind with thiol group of Cys-315 of KOR, we synthesized a series of Michael-acceptor type of salvinorin A derivatives, and evaluated for their binding affinity at κ-, µ-, and δ-opioid receptors.
Acknowledgements: This work was supported by the NIH Grant R01 DA017204 and the NIMH Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill, NC 27599. References:  Roth BL, et al. (2002) Proc Natl Acad Sci, 99: 11934 – 11939.  Cunningham CW et al. (2011) Pharmacol Rev, 63: 316 – 347.  Yan F, et al. (2009) Biochemistry, 48: 6898 – 6908.