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

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

  • J Med Chem. 2020 Jan 23;63(2):542-568. doi: 10.1021/acs.jmedchem.9b01142.
Sumanta Garai 1,  Pushkar M Kulkarni 1,  Peter C Schaffer 1,  Luciana M Leo 2,  Asher L Brandt 3,  Ayat Zagzoog 3,  Tallan Black 3,  Xiaoyan Lin 4,  Dow P Hurst 5,  David R Janero 6,  Mary E Abood 2,  Anaelle Zimmowitch 4,  Alex Straiker 4,  Roger G Pertwee 7,  Melanie Kelly 8,  Anna-Maria Szczesniak 8,  Eileen M Denovan-Wright 8,  Ken Mackie 4,  Andrea G Hohmann 4,  Patricia H Reggio 5,  Robert B Laprairie 3 8,  Ganesh A Thakur 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences , Northeastern University , Boston , Massachusetts 02115 , United States.
  • 2 Center for Substance Abuse Research, Lewis Katz School of Medicine , Temple University , Philadelphia , Pennsylvania 19140 , United States.
  • 3 College of Pharmacy and Nutrition , University of Saskatchewan , 104 Clinic Pl , Saskatoon , SK S7N2Z4 , Canada.
  • 4 Program in Neuroscience, Psychological and Brain Sciences, and Gill Center for Biomolecular Science , Indiana University , Bloomington , Indiana 47405 , United States.
  • 5 Center for Drug Discovery , University of North Carolina Greensboro , Greensboro , North Carolina 27402 , United States.
  • 6 Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Department of Chemistry and Chemical Biology, College of Science, and Health Sciences Entrepreneurs , Northeastern University , Boston , Massachusetts 02115 , United States.
  • 7 School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences , University of Aberdeen , Aberdeen AB25 2ZD , Scotland, U.K.
  • 8 Department of Pharmacology, Faculty of Medicine , Dalhousie University , 5850 College St , Halifax , NS , B3H4R2 , Canada.
PMID: 31756109 DOI: 10.1021/acs.jmedchem.9b01142
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.

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