Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy ()

Sumanta Garai; Luciana M. Leo; Anna Maria Szczesniak; Dow P. Hurst; Peter C. Schaffer; Ayat Zagzoog; Tallan Black; Jeffrey R. Deschamps; Elke Miess; Stefan Schulz; David R. Janero; Alex Straiker; Roger G. Pertwee; Mary E. Abood; Melanie E.M. Kelly; Patricia H. Reggio; Robert B. Laprairie; Ganesh A. Thakur

doi:10.1021/acs.jmedchem.1c00040

Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy ()

Sumanta Garai, Luciana M. Leo, Anna Maria Szczesniak, Dow P. Hurst, Peter C. Schaffer, Ayat Zagzoog, Tallan Black, Jeffrey R. Deschamps, Elke Miess, Stefan Schulz, David R. Janero, Alex Straiker, Roger G. Pertwee, Mary E. Abood, Melanie E.M. Kelly, Patricia H. Reggio, Robert B. Laprairie, Ganesh A. Thakur

Medicine

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26 Citations (Scopus)

Abstract

We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy oferythro, (±)-vsthreo, (±)-constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9enantiomers, (−)-(S,R)-13evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (−)-(S,R)-13and (+)-(R,S)-14were devoid of undesirable side effects (triad test), and (+)-(R,S)-14reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (−)-(S,R)-13docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.

Original language	English
Pages (from-to)	8104-8126
Number of pages	23
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	12
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00040
Publication status	Published - Jun 24 2021

Bibliographical note

Funding Information:
This work was supported by EY024727 (to G.A.T., R.G.P., A.S., and M.E.M.K.), R01 DA045698, T32 DA007237, and P30 DA013429 (to M.E.A. and L.M.L), a partnership grant to RBL from GlaxoSmithKline and the Canadian Institutes of Health Research (CIHR) (201704), and a Project Grant to RBL (201909). T.B. and A.Z. are supported by research scholarships from the College of Pharmacy and Nutrition, University of Saskatchewan.

Publisher Copyright:
© 2021 American Chemical Society

ASJC Scopus Subject Areas

Molecular Medicine
Drug Discovery

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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Garai, S., Leo, L. M., Szczesniak, A. M., Hurst, D. P., Schaffer, P. C., Zagzoog, A., Black, T., Deschamps, J. R., Miess, E., Schulz, S., Janero, D. R., Straiker, A., Pertwee, R. G., Abood, M. E., Kelly, M. E. M., Reggio, P. H., Laprairie, R. B., & Thakur, G. A. (2021). Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy (). Journal of Medicinal Chemistry, 64(12), 8104-8126. https://doi.org/10.1021/acs.jmedchem.1c00040

Garai, S, Leo, LM, Szczesniak, AM, Hurst, DP, Schaffer, PC, Zagzoog, A, Black, T, Deschamps, JR, Miess, E, Schulz, S, Janero, DR, Straiker, A, Pertwee, RG, Abood, ME, Kelly, MEM, Reggio, PH, Laprairie, RB & Thakur, GA 2021, 'Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy ()', Journal of Medicinal Chemistry, vol. 64, no. 12, pp. 8104-8126. https://doi.org/10.1021/acs.jmedchem.1c00040

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title = "Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy ()",

abstract = "We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy oferythro, (±)-vsthreo, (±)-constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9enantiomers, (−)-(S,R)-13evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (−)-(S,R)-13and (+)-(R,S)-14were devoid of undesirable side effects (triad test), and (+)-(R,S)-14reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (−)-(S,R)-13docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.",

author = "Sumanta Garai and Leo, {Luciana M.} and Szczesniak, {Anna Maria} and Hurst, {Dow P.} and Schaffer, {Peter C.} and Ayat Zagzoog and Tallan Black and Deschamps, {Jeffrey R.} and Elke Miess and Stefan Schulz and Janero, {David R.} and Alex Straiker and Pertwee, {Roger G.} and Abood, {Mary E.} and Kelly, {Melanie E.M.} 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.G.P., A.S., and M.E.M.K.), R01 DA045698, T32 DA007237, and P30 DA013429 (to M.E.A. and L.M.L), a partnership grant to RBL from GlaxoSmithKline and the Canadian Institutes of Health Research (CIHR) (201704), and a Project Grant to RBL (201909). T.B. and A.Z. are supported by research scholarships from the College of Pharmacy and Nutrition, University of Saskatchewan. Publisher Copyright: {\textcopyright} 2021 American Chemical Society",

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doi = "10.1021/acs.jmedchem.1c00040",

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T2 - Preclinical Anti-Glaucoma Efficacy ()

AU - Garai, Sumanta

AU - Leo, Luciana M.

AU - Szczesniak, Anna Maria

AU - Hurst, Dow P.

AU - Schaffer, Peter C.

AU - Zagzoog, Ayat

AU - Black, Tallan

AU - Deschamps, Jeffrey R.

AU - Miess, Elke

AU - Schulz, Stefan

AU - Janero, David R.

AU - Straiker, Alex

AU - Pertwee, Roger G.

AU - Abood, Mary E.

AU - Kelly, Melanie E.M.

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.G.P., A.S., and M.E.M.K.), R01 DA045698, T32 DA007237, and P30 DA013429 (to M.E.A. and L.M.L), a partnership grant to RBL from GlaxoSmithKline and the Canadian Institutes of Health Research (CIHR) (201704), and a Project Grant to RBL (201909). T.B. and A.Z. are supported by research scholarships from the College of Pharmacy and Nutrition, University of Saskatchewan. Publisher Copyright: © 2021 American Chemical Society

PY - 2021/6/24

Y1 - 2021/6/24

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Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy ()

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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