Resumen
Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, β-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
Idioma original | English |
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Páginas (desde-hasta) | 542-568 |
Número de páginas | 27 |
Publicación | Journal of Medicinal Chemistry |
Volumen | 63 |
N.º | 2 |
DOI | |
Estado | Published - ene. 23 2020 |
Nota bibliográfica
Funding Information:This work was supported by EY024727 (to G.A.T., R.P., A.S., and M.K.), DA047858 (to A.G.H. and K.M.), DA041229 (to A.G.H. and K.M.), DA009158 (to A.G.H., K.M., and M.E.A.), DA013429 (to M.E.A. and L.M.L.), DA007327 (to L.M.L.), DA045698 (to M.E.A. and P.H.R.), and DA003934 (to P.H.R.). This research was also funded with support through a partnership grant to R.B.L. from GlaxoSmithKline and the Canadian Institutes of Health Research (386427). T.B. is supported by a research scholarship from the College of Pharmacy and Nutrition, University of Saskatchewan.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
ASJC Scopus Subject Areas
- Molecular Medicine
- Drug Discovery