2. Academic Validation
  3. Focused structure-activity relationship profiling around the 2-phenylindole scaffold of a cannabinoid type-1 receptor agonist-positive allosteric modulator: site-III aromatic-ring congeners with enhanced activity and solubility

Focused structure-activity relationship profiling around the 2-phenylindole scaffold of a cannabinoid type-1 receptor agonist-positive allosteric modulator: site-III aromatic-ring congeners with enhanced activity and solubility

  • Bioorg Med Chem. 2020 Nov 1;28(21):115727. doi: 10.1016/j.bmc.2020.115727.
Peter C Schaffer 1,  Pushkar M Kulkarni 1,  David R Janero 2,  Ganesh A Thakur 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, United States.
  • 2 Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, United States; Health Sciences Entrepreneurs, Northeastern University, Boston, MA 02115, United States.
  • 3 Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, United States. Electronic address: g.thakur@northeastern.edu.
PMID: 33065437 DOI: 10.1016/j.bmc.2020.115727
Abstract

Specific tuning of cannabinoid 1 receptor (CB1R) activity by small-molecule allosteric modulators is a therapeutic modality with multiple properties inherently advantageous to therapeutic applications. We previously generated a library of unique CB1R positive allosteric modulators (PAMs) derived from GAT211, which has three pharmacophoric sites critical to its ago-PAM activity. To elaborate our CB1R PAM library, we report the rational design and molecular-pharmacology profiling of several 2-phenylindole analogs modified at the "site-III" aromatic ring. The comprehensive structure-activity relationship (SAR) investigation demonstrates that attaching small lipophilic functional groups on the ortho-position of the GAT211 site-III phenyl ring could markedly enhance CB1R ago-PAM activity. Select site-III modifications also improved GAT211's water solubility. The SAR reported both extends the structural diversity of this compound class and demonstrates the utility of GAT211's site-III for improving the parent compound's drug-like properties of potency and/or aqueous solubility.

Keywords

2-Phenylindole; Cannabinoid type-1 receptor; Functional selectivity; Physiochemical properties; Positive allosteric modulator.

Figures
Products