Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

Sumanta Garai; Pushkar M. Kulkarni; Peter C. Schaffer; Luciana M. Leo; Asher L. Brandt; Ayat Zagzoog; Tallan Black; Xiaoyan Lin; Dow P. Hurst; David R. Janero; Mary E. Abood; Anaelle Zimmowitch; Alex Straiker; Roger G. Pertwee; Melanie Kelly; Anna Maria Szczesniak; Eileen M. Denovan-Wright; Ken Mackie; Andrea G. Hohmann; Patricia H. Reggio; Robert B. Laprairie; Ganesh A. Thakur

doi:10.1021/acs.jmedchem.9b01142

Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

Sumanta Garai, Pushkar M. Kulkarni, Peter C. Schaffer, Luciana M. Leo, Asher L. Brandt, Ayat Zagzoog, Tallan Black, Xiaoyan Lin, Dow P. Hurst, David R. Janero, Mary E. Abood, Anaelle Zimmowitch, Alex Straiker, Roger G. Pertwee, Melanie Kelly, Anna Maria Szczesniak, Eileen M. Denovan-Wright, Ken Mackie, Andrea G. Hohmann, Patricia H. ReggioRobert B. Laprairie, Ganesh A. Thakur

Medicine

Résultat de recherche: Article › examen par les pairs

47 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Pages (de-à)	542-568
Nombre de pages	27
Journal	Journal of Medicinal Chemistry
Volume	63
Numéro de publication	2
DOI	https://doi.org/10.1021/acs.jmedchem.9b01142
Statut de publication	Published - janv. 23 2020

Note bibliographique

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

Accès au document

10.1021/acs.jmedchem.9b01142

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Citer

Garai, S., Kulkarni, P. M., Schaffer, P. C., Leo, L. M., Brandt, A. L., Zagzoog, A., Black, T., Lin, X., Hurst, D. P., Janero, D. R., Abood, M. E., Zimmowitch, A., Straiker, A., Pertwee, R. G., Kelly, M., Szczesniak, A. M., Denovan-Wright, E. M., Mackie, K., Hohmann, A. G., ... Thakur, G. A. (2020). Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators. Journal of Medicinal Chemistry, 63(2), 542-568. https://doi.org/10.1021/acs.jmedchem.9b01142

Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators. / Garai, Sumanta; Kulkarni, Pushkar M.; Schaffer, Peter C. et al.
Dans: Journal of Medicinal Chemistry, Vol. 63, N° 2, 23.01.2020, p. 542-568.

Résultat de recherche: Article › examen par les pairs

Garai, S, Kulkarni, PM, Schaffer, PC, Leo, LM, Brandt, AL, Zagzoog, A, Black, T, Lin, X, Hurst, DP, Janero, DR, Abood, ME, Zimmowitch, A, Straiker, A, Pertwee, RG, Kelly, M , Szczesniak, AM , Denovan-Wright, EM, Mackie, K, Hohmann, AG, Reggio, PH, Laprairie, RB & Thakur, GA 2020, 'Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators', Journal of Medicinal Chemistry, vol. 63, n° 2, pp. 542-568. https://doi.org/10.1021/acs.jmedchem.9b01142

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title = "Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators",

abstract = "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.",

author = "Sumanta Garai and Kulkarni, {Pushkar M.} and Schaffer, {Peter C.} and Leo, {Luciana M.} and Brandt, {Asher L.} and Ayat Zagzoog and Tallan Black and Xiaoyan Lin and Hurst, {Dow P.} and Janero, {David R.} and Abood, {Mary E.} and Anaelle Zimmowitch and Alex Straiker and Pertwee, {Roger G.} and Melanie Kelly and Szczesniak, {Anna Maria} and Denovan-Wright, {Eileen M.} and Ken Mackie and Hohmann, {Andrea G.} and Reggio, {Patricia H.} and Laprairie, {Robert B.} and Thakur, {Ganesh A.}",

note = "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 {\textcopyright} 2019 American Chemical Society.",

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T1 - Application of Fluorine- And Nitrogen-Walk Approaches

T2 - Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators

AU - Garai, Sumanta

AU - Kulkarni, Pushkar M.

AU - Schaffer, Peter C.

AU - Leo, Luciana M.

AU - Brandt, Asher L.

AU - Zagzoog, Ayat

AU - Black, Tallan

AU - Lin, Xiaoyan

AU - Hurst, Dow P.

AU - Janero, David R.

AU - Abood, Mary E.

AU - Zimmowitch, Anaelle

AU - Straiker, Alex

AU - Pertwee, Roger G.

AU - Kelly, Melanie

AU - Szczesniak, Anna Maria

AU - Denovan-Wright, Eileen M.

AU - Mackie, Ken

AU - Hohmann, Andrea G.

AU - Reggio, Patricia H.

AU - Laprairie, Robert B.

AU - Thakur, Ganesh A.

N1 - 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.

PY - 2020/1/23

Y1 - 2020/1/23

N2 - 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.

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