Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

Alexander M. Sherwood; Rachel Saylor Crowley; Kelly F. Paton; Andrew Biggerstaff; Benjamin Neuenswander; Victor W. Day; Bronwyn M. Kivell; Thomas E. Prisinzano

doi:10.1021/acs.jmedchem.7b00148

Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

Alexander M. Sherwood, Rachel Saylor Crowley, Kelly F. Paton, Andrew Biggerstaff, Benjamin Neuenswander, Victor W. Day, Bronwyn M. Kivell, Thomas E. Prisinzano

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	3866-3878
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	9
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00148
State	Published - May 11 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

Funding

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.

Funders	Funder number
National Science Foundation (NSF)	0320648
National Institutes of Health (NIH)
National Center for Research Resources	S10RR024664
Health Research Council of New Zealand

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.7b00148

Cite this

Sherwood, A. M., Crowley, R. S., Paton, K. F., Biggerstaff, A., Neuenswander, B., Day, V. W., Kivell, B. M., & Prisinzano, T. E. (2017). Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability. Journal of Medicinal Chemistry, 60(9), 3866-3878. https://doi.org/10.1021/acs.jmedchem.7b00148

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abstract = "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.",

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AU - Biggerstaff, Andrew

AU - Neuenswander, Benjamin

AU - Day, Victor W.

AU - Kivell, Bronwyn M.

AU - Prisinzano, Thomas E.

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Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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