title: Characterization of a novel, brain-penetrating CB1 receptor inverse agonist: metabolic profile in diet-induced obese models and aspects of central activity.
abstract: Pharmacologic antagonism of cannabinoid 1 receptors (CB1 receptors) in the central nervous system (CNS) suppresses food intake, promotes weight loss, and improves the metabolic profile. Since the CB1 receptor is expressed both in the CNS and in peripheral tissues, therapeutic value may be gained with CB1 receptor inverse agonists acting on receptors in both domains. The present report examines the metabolic and CNS actions of a novel CB1 receptor inverse agonist, compound 64, a 1,5,6-trisubstituted pyrazolopyrimidinone. Compound 64 showed similar or superior binding affinity, in vitro potency, and pharmacokinetic profile compared to rimonabant. Both compounds improved the metabolic profile in diet-induced obese (DIO) rats and obese cynomolgus monkeys. Weight loss tended to be greater in compound 64-treated DIO rats compared to pair-fed counterparts, suggesting that compound 64 may have metabolic effects beyond those elicited by weight loss alone. In the CNS, reversal of agonist-induced hypothermia and hypolocomotion indicated that compound 64 possessed an antagonist activity in vivo. Dosed alone, compound 64 suppressed extinction of conditioned freezing (10 mg/kg) and rapid eye movement (REM) sleep (30 mg/kg), consistent with previous reports for rimonabant, although for REM sleep, compound 64 was greater than threefold less potent than for metabolic effects. Together, these data suggested that (1) impairment of extinction learning and REM sleep suppression are classic, centrally mediated responses to CB1 receptor inverse agonists, and (2) some separation may be achievable between central and peripheral effects with brain-penetrating CB1 receptor inverse agonists while maintaining metabolic efficacy. Furthermore, chronic treatment with compound 64 contributes to evidence that peripheral CB1 receptor blockade may yield beneficial outcomes that exceed those elicited by weight loss alone.
authors.affiliation: Neuroscience Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland. laura.jacobson@novartis.com
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.forename: S Renee
authors.initials: SR
authors.lastname: Commerford
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Gerber
authors.forename: Yu Alice
authors.initials: YA
authors.lastname: Chen
authors.forename: Beatriz
authors.initials: B
authors.lastname: Dardik
authors.forename: Frederique
authors.initials: F
authors.lastname: Chaperon
authors.forename: Chad
authors.initials: C
authors.lastname: Schwartzkopf
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen-Tran
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollenbeck
authors.forename: Peter
authors.initials: P
authors.lastname: McNamara
authors.forename: Xiaohui
authors.initials: X
authors.lastname: He
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.forename: Anne-Liese
authors.initials: AL
authors.lastname: Jaton
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: Sandra
authors.initials: S
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005108:Extinction, Psychological / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D012895:Sleep, REM / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: C570926:5-(4-chloro-phenyl)-1-phenyl-6-(4-pyrazin-2-yl-phenyl)-1,5-dihydro-pyrazolo(3,4-d)pyrimidin-4-one; D010880:Piperidines; D011720:Pyrazoles; D011744:Pyrimidinones; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant