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

Abstract

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.

Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution

“…In previous studies conducted by our group and others, 22, 23 the 6-pyrrolidinyl group on the pyridine ring of 2 was either retained or replaced with substituted amino groups such as dimethylamino ( 6 ), which can be seen as the ring opened analogs of the pyrrolidinyl ring. To explore the importance of the pyrrolidinyl substituent on the allosteric modulating activity, we first replaced the pyrrolidinyl ring with another hydrogen bond acceptor, a methoxy group.…”

Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities

“…The two compounds show similar profiles for their impact on CP55,940 binding and its G-protein coupling, i.e. increased binding of CP55,940, together with antagonism of CP55,940 induced G-protein coupling (Horswill et al, 2010; Khurana et al, 2017). Similar to ORG27569, PSNCBAM-1 demonstrates biased signaling via β-arrestin 1 as seen in ERK1/2 phosphorylation studies (Khurana et al, 2017).…”

“…increased binding of CP55,940, together with antagonism of CP55,940 induced G-protein coupling (Horswill et al, 2010; Khurana et al, 2017). Similar to ORG27569, PSNCBAM-1 demonstrates biased signaling via β-arrestin 1 as seen in ERK1/2 phosphorylation studies (Khurana et al, 2017). Like ORG25769, PSNCBAM-1 behaves as an inhibitor of 2-AG-mediated inhibition of synaptic transmission (Straiker et al, 2015).…”

“…German and colleagues (German et al, 2014) utilized calcium mobilization assays whereas Kendall and group utilized radioligand binding assays to generate a SAR for PSNCBAM-1 (Khurana et al, 2017). Key findings of the SAR include (1) Non-cyclic substitutions such as a dimethylamino group at the 2-pyrrolidinylpyridine position of PSNCBAM-1 are more favored at this position (German et al, 2014), and (2) there needs to be an electron-withdrawing substituent at the 4-chorophenyl position with a cyano group being more potent than a chloro group (German et al, 2014; Khurana et al, 2017). However, other electron-withdrawing groups such as COOH, CF 3 , acetyl or ethoxyacyl groups do not demonstrate high affinity or cooperativity in radioligand binding assays compared to the cyano group (Khurana et al, 2017).…”

“…(3) The position of the electron-withdrawing group is critical. Change in the cyano group from para to meta position drastically reduced affinity and efficacy of the allosteric modulator (Khurana et al, 2017). …”