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Characterization of a novel, brain-penetrating CB1 receptor inverse agonist: metabolic profile in diet-induced obese models and aspects of central activity

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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.

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Abbreviations

AUC:

Area under the curve

β-OHB:

β-hydroxybutyrate

CB1 receptor:

Cannabinoid receptor 1

C max :

Maximal plasma drug concentration

CNS:

Central nervous system

DIO:

Diet-induced obese model

ECS:

Endocannabinoid system

F%:

Oral bioavailability

hCB1 receptor:

Human CB1 receptor

hCB2 receptor:

Human CB2 receptor

IC50 :

Half maximal inhibitory concentration

iv:

Intravenous

NEFA:

Non-esterified free fatty acids

PEG:

Polyethylene glycol

PK:

Pharmacokinetic

PD:

Pharmacodynamic

REM:

Rapid eye movement

RER:

Respiratory exchange ratio

t 1/2 :

Terminal elimination half-life

T2DM:

Type 2 diabetes

Tg:

Triglyceride

TChol:

Total cholesterol

t max :

Time of maximal drug concentration

VDss:

Volume of distribution at steady state

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Acknowledgements

We thank Stephen Marmor, Diana Dubiel, Hayley Crowe, and Korina Veenstra for help with plasma analytical work; Weijia Zheng for help with formulation work; Michael Hayes and Albert Enz for compound bioanalytical work; Liladhar Waykole for help with compound manufacturing. We gratefully acknowledge the expert contributions of Xianglin Ren, Anton Neuenschwander, Charlotte Huber, Margrit Zingg, Tove Tuntland, Mark Perrone, Jeremy Caldwell, Donald S. Karanewsky, Kunyong Yang, Alan Chu, Cara Cuc T. Ngo, and David Huang for advice and assistance with study design, execution, and data evaluation. We gratefully thank Prof. Daniel Hoyer for critical reading of the manuscript and associated advice.

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Authors and Affiliations

  1. Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    S. Renee Commerford, Sarah P. Gerber, Beatriz Dardik, Chad Schwartzkopf, Jesper Gromada & Sandra Teixeira

  2. Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA

    Yu Alice Chen, Van Nguyen-Tran, Thomas Hollenbeck, Peter McNamara, Xiaohui He, Hong Liu & H. Martin Seidel

  3. Neuroscience Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland

    Laura H. Jacobson, Frederique Chaperon & Anne-Liese Jaton

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  1. Laura H. Jacobson
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Correspondence to Laura H. Jacobson.

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Laura H. Jacobson and S. Renee Commerford contributed equally to this manuscript.

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Jacobson, L.H., Commerford, S.R., Gerber, S.P. et al. Characterization of a novel, brain-penetrating CB1 receptor inverse agonist: metabolic profile in diet-induced obese models and aspects of central activity. Naunyn-Schmiedeberg's Arch Pharmacol 384, 565–581 (2011). https://doi.org/10.1007/s00210-011-0686-y

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