Focused structure-activity relationship profiling around the 2-phenylindole scaffold of a cannabinoid type-1 receptor
Peter C Schaffer1, Pushkar M Kulkarni1, David R Janero2
1Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, United States.
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.
More Related Videos
07:30A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones
Published on: January 21, 2020
05:50Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Related Concept Videos
Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
The direct-acting...
ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3
Drug-Receptor Interaction: Agonist
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
