title: Diarylureas as allosteric modulators of the cannabinoid CB1 receptor: structure-activity relationship studies on 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1).
abstract: The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (4) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on 4, we have designed and synthesized a series of analogs focusing on modifications at two positions. Pharmacological evaluation in calcium mobilization and binding assays revealed the importance of alkyl substitution at the 2-aminopyridine moiety and electron deficient aromatic groups at the 4-chlorophenyl position for activity at the CB1 receptor, resulting in several analogs with comparable potency to 4. These compounds increased the specific binding of [(3)H]CP55,940, in agreement with previous reports. Importantly, 4 and two analogs dose-dependently reduced the Emax of the agonist curve in the CB1 calcium mobilization assays, confirming their negative allosteric modulator characteristics. Given the side effects associated with CB1 receptor orthosteric antagonists, negative allosteric modulators provide an alternative approach to modulate the pharmacologically important CB1 receptor.
authors.affiliation: Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: German
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Gay
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry* / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C526691:1-(4-chlorophenyl)-3-(3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl)urea; D010671:Phenylurea Compounds; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D002118:Calcium