Structural Optimization of the Diarylurea PSNCBAM-1, an Allosteric Modulator of Cannabinoid Receptor 1.

Background: Structure-activity relationship studies improve the pharmacological and pharmacokinetic properties of a lead compound such as PSNCBAM-1, an allosteric modulator of the cannabinoid receptor 1.

Objectives: Here, several derivatives of PSNCBAM-1 were synthesized with the aim of reducing the number of rings within its structure and enhancing the solubility of the compounds. The derivatives studied contain substituents previously shown to enhance binding of agonists (ie, a cyano group and a pyrimidine ring), with a reduced number of rings compared with the parent compound, PSNCBAM-1.

Allosteric modulators restore orthosteric agonist binding to mutated CB receptors.

Objectives: To determine if diminished orthosteric agonist binding due to mutations in extracellular loops 1 or 2 of the cannabinoid receptor 1 (CB ) can be overcome by an allosteric modulator and restore agonist binding.

Methods: Binding assays were performed using a range of concentrations of orthosteric compound, in the presence or absence of a set concentration of the allosteric modulator PSNCBAM-1 to determine the EC in its absence or presence.

Key Findings: Single mutations in extracellular loop 1 or 2 of CB showed weak or no binding of agonist CP55940 to the receptor.

Exploring 6-Azaindole and 7-Azaindole Rings for Developing Cannabinoid Receptor 1 Allosteric Modulators.

Org27569 is a prototypical allosteric modulator of the cannabinoid receptor 1 (CB). It belongs to the indole-2-carboxamide scaffold and has been intensively investigated in pharmacology and in structure-activity relationship (SAR) studies. Although azaindoles are rare in natural products and differ only by the presence of an extra ring nitrogen, they were demonstrated as valuable bioisosteres in many pharmacologically important molecules.

Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes.

Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two Gprotein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors.