Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor.
Prabhakar R Polepally, Krzysztof Huben, Eyal Vardy, Vincent Setola, Philip D Mosier, Bryan L. Roth, Jordan K Zjawiony
European journal of medicinal chemistry October 6, 2014 DOI: 10.1016/j.ejmech.2014.07.077 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Keywords | Michael acceptor-type ligands Molecular modeling |
| Citations | 28 |
| Key findings | New salvinorin A derivatives with Michael acceptor groups at C-2 show high affinity for the κ-opioid receptor, with some also binding to the μ-opioid receptor, but none exhibit wash-resistant irreversible binding. |
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.