Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a κ-opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone 14, was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50 = 0.6 ± 0.2 nM at κ; >10000 nM at μ and δ). Microsomal stability studies demonstrated that 14 was more metabolically resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory properties revealed similar in vivo effects between 14 and salvinorin A. To our knowledge, this study represents the first example of bioisosteric replacement of an acetate group by a spirobutyrolactone to produce a metabolically resistant derivative.
|Number of pages||13|
|Journal||Journal of Medicinal Chemistry|
|State||Published - May 11 2017|
Bibliographical noteFunding Information:
This work was supported by DA018151, GM111385 (to T.E.P.), GM008545 (to R.S.C.), AFPE Predoctoral Fellowship in Pharmaceutical Sciences (to R.S.C.), and the Health Research Council of New Zealand (to B.M.K.). Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant no. S10RR024664 and NSF Major Research Instrumentation Grant no. 0320648.
© 2017 American Chemical Society.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery