title: 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 CB1antagonist 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 CB1ligands, 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 CB1orthosteric 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 CB1allosteric modulators that show biased agonism and potentially antiobesity behavior via a new mechanism.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Leepakshi
authors.initials: L
authors.lastname: Khurana
authors.affiliation: Rangel College of Pharmacy, Health Science Center, Texas A&M University , 1010 West Avenue B, Kingsville, Texas 78363, United States.
authors.forename: Bo-Qiao
authors.initials: BQ
authors.lastname: Fu
authors.affiliation: Rangel College of Pharmacy, Health Science Center, Texas A&M University , 1010 West Avenue B, Kingsville, Texas 78363, United States.
authors.forename: Anantha L
authors.initials: AL
authors.lastname: Duddupudi
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Yu-Hsien
authors.initials: YH
authors.lastname: Liao
authors.affiliation: Rangel College of Pharmacy, Health Science Center, Texas A&M University , 1010 West Avenue B, Kingsville, Texas 78363, United States.
authors.forename: Sri Sujana
authors.initials: SS
authors.lastname: Immadi
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Kendall
authors.affiliation: Rangel College of Pharmacy, Health Science Center, Texas A&M University , 1010 West Avenue B, Kingsville, Texas 78363, United States.
authors.forename: Dai
authors.identifier: 0000-0003-2630-3184
authors.initials: D
authors.lastname: Lu
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D006801:Humans; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D014508:Urea / Q000031:analogs & derivatives*
chemical_list: D011743:Pyrimidines; D043884:Receptor, Cannabinoid, CB1; D014508:Urea