Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CB₁

The
allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)­pyridin-2-yl)­phenyl)­urea
(PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB1) and antagonized G protein coupling. This compound demonstrated
potent anorectic effects similar to the CB1 antagonist
rimonabant that once was marketed for the treatment of obesity, suggesting
a new chemical entity for the discovery of antiobesity drugs. To increase
structural diversity of this class of CB1 ligands, we designed
and synthesized two classes of novel analogues, in which the pyridine
ring of 2 was replaced by a pyrimidine ring. These positively
modulate the binding of the CB1 orthosteric agonist CP55,940
while exhibiting an antagonism of G-protein coupling activity. Interestingly,
compounds 7d and 8d demonstrated ERK1/2
phosphorylation mediated via β-arrestin unlike the orthosteric
CP55,940 that does so in a G protein-dependent manner. These can serve
as new lead compounds for the future development of CB1 allosteric modulators that show biased agonism and potentially antiobesity
behavior via a new mechanism.