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

• New potential Michael acceptor analogues of salvinorin A were synthesized.
• Compounds were evaluated for binding affinity at κ-, δ-, and μ-opioid receptors.
• Molecular modeling studies describe putative binding modes for the compounds.
• Most compounds have high binding affinity at κ; 5a has dual affinity for κ and μ.
• 5a could be developed as a potent CNS or peripheral drug in the near future.

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.

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