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

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 exhi...

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Vydané v:Journal of medicinal chemistry Ročník 63; číslo 2; s. 542 - 568
Hlavní autori: Garai, Sumanta, Kulkarni, Pushkar M., Schaffer, Peter C., Leo, Luciana M., Brandt, Asher L., Zagzoog, Ayat, Black, Tallan, Lin, Xiaoyan, Hurst, Dow P., Janero, David R., Abood, Mary E., Zimmowitch, Anaelle, Straiker, Alex, Pertwee, Roger G., Kelly, Melanie, Szczesniak, Anna-Maria, Denovan-Wright, Eileen M., Mackie, Ken, Hohmann, Andrea G., Reggio, Patricia H., Laprairie, Robert B., Thakur, Ganesh A.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: WASHINGTON Amer Chemical Soc 23.01.2020
Predmet:
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
NEUROPATHIC PAIN
DESIGN
CB1
PROTEIN
AGONISM
SIGNALING SYSTEM
ENDOCANNABINOID SYSTEM
INTRAOCULAR-PRESSURE
SELECTIVITY
STRATEGIES
ISSN:0022-2623, 1520-4804, 1520-4804
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Shrnutí: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, beta-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. [GRAPHICS] .
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.9b01142