PSNCBAM-1 analogs: Structural evolutions and allosteric properties at cannabinoid CB1 receptor

Area of Science:

• Medicinal Chemistry
• Neuropharmacology
• Molecular Biology

Background:

• Allosteric modulation of cannabinoid receptor type 1 (CB1R) offers a therapeutic strategy distinct from orthosteric stimulation, potentially avoiding adverse effects.
• PSNCBAM-1, a diaryl urea derivative, serves as a reference compound, exhibiting both positive allosteric modulator (PAM) and negative allosteric modulator (NAM) properties at CB1Rs.

Purpose of the Study:

• To design, synthesize, and biologically evaluate novel CB1R allosteric modulators based on structural modifications of PSNCBAM-1 and related analogs.
• To extend the understanding of structure-activity relationships for CB1R allosteric modulators.

Main Methods:

• Synthesis of three series of novel compounds derived from PSNCBAM-1.
• Evaluation of binding affinity for orthosteric ligands at CB1Rs.
• Functional assays ([35S]GTPγS) to determine PAM and NAM activity in the presence and absence of an orthosteric agonist.

Main Results:

• Most synthesized compounds demonstrated a PAM profile, enhancing the binding affinity of the orthosteric ligand CP55940 at CB1Rs.
• Compounds 11 and 18 exhibited functional NAM activity, significantly reducing orthosteric agonist-induced CB1R activity by approximately 30% in the [35S]GTPγS assay.
• The study identified new CB1R allosteric modulators with profiles similar to the reference compound PSNCBAM-1.

Conclusions:

• The structural modifications led to the discovery of novel CB1R allosteric modulators.
• The findings contribute to the structure-activity relationship knowledge for CB1R allosteric modulators, paving the way for potential therapeutic applications.