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 Peer reviewed DOI: 10.1016/j.ejmech.2014.07.077 via PubMed
Summary
Salvinorin A, a compound from Salvia divinorum, has a strong affinity for the κ-opioid receptor (KOR). A new series of derivatives of salvinorin A was synthesized to explore their interactions with KOR, δ-opioid receptor (DOR), and μ-opioid receptor (MOR). While none of the derivatives demonstrated irreversible binding, most showed high affinity for KOR, with some also having dual affinity for KOR and MOR. Molecular modeling techniques were utilized to understand these interactions.
Study at a glance
| Key finding | Most salvinorin A derivatives synthesized showed high affinity for the κ-opioid receptor, with some exhibiting dual affinity for both KOR and MOR. |
|---|
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.