Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593

Asher L. Brandt; Sumanta Garai; Ayat Zagzoog; Dow P. Hurst; Lesley A. Stevenson; Roger G. Pertwee; Gregory H. Imler; Patricia H. Reggio; Ganesh A. Thakur; Robert B. Laprairie

doi:10.3389/fphar.2022.919605

Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593

Asher L. Brandt, Sumanta Garai, Ayat Zagzoog, Dow P. Hurst, Lesley A. Stevenson, Roger G. Pertwee, Gregory H. Imler, Patricia H. Reggio, Ganesh A. Thakur, Robert B. Laprairie

Medicine

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3 Citas (Scopus)

Resumen

Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo. The R-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro, and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington’s disease.

Idioma original	English
Número de artículo	919605
Publicación	Frontiers in Pharmacology
Volumen	13
DOI	https://doi.org/10.3389/fphar.2022.919605
Estado	Published - oct. 25 2022

Nota bibliográfica

Funding Information:
This work was supported by a GlaxoSmithKline (GSK)-Canadian Institutes of Health Research (CIHR) partnership grant (201704) and a CIHR Project Grant (201909) held by RL and a National Institutes of Health (NIH) R01 to GAT (EY024727). AZ is supported by a graduate scholarship from the College of Pharmacy and Nutrition, University of Saskatchewan. In silico modeling studies were supported by the NIH to PR (DA003934). The x-ray crystallographic work was supported by NIDA through Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL).

Publisher Copyright:
Copyright © 2022 Brandt, Garai, Zagzoog, Hurst, Stevenson, Pertwee, Imler, Reggio, Thakur and Laprairie.

ASJC Scopus Subject Areas

Pharmacology
Pharmacology (medical)

PubMed: MeSH publication types

Journal Article

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Brandt, A. L., Garai, S., Zagzoog, A., Hurst, D. P., Stevenson, L. A., Pertwee, R. G., Imler, G. H., Reggio, P. H., Thakur, G. A., & Laprairie, R. B. (2022). Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593. Frontiers in Pharmacology, 13, Artículo 919605. https://doi.org/10.3389/fphar.2022.919605

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title = "Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593",

abstract = "Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo. The R-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro, and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington{\textquoteright}s disease.",

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note = "Funding Information: This work was supported by a GlaxoSmithKline (GSK)-Canadian Institutes of Health Research (CIHR) partnership grant (201704) and a CIHR Project Grant (201909) held by RL and a National Institutes of Health (NIH) R01 to GAT (EY024727). AZ is supported by a graduate scholarship from the College of Pharmacy and Nutrition, University of Saskatchewan. In silico modeling studies were supported by the NIH to PR (DA003934). The x-ray crystallographic work was supported by NIDA through Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). Publisher Copyright: Copyright {\textcopyright} 2022 Brandt, Garai, Zagzoog, Hurst, Stevenson, Pertwee, Imler, Reggio, Thakur and Laprairie.",

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AU - Brandt, Asher L.

AU - Garai, Sumanta

AU - Zagzoog, Ayat

AU - Hurst, Dow P.

AU - Stevenson, Lesley A.

AU - Pertwee, Roger G.

AU - Imler, Gregory H.

AU - Reggio, Patricia H.

AU - Thakur, Ganesh A.

AU - Laprairie, Robert B.

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PY - 2022/10/25

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Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593

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Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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