Chilly-Mazarin, France
Chilly-Mazarin, France

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Griebel G.,Sanofi S.A. | Pichat P.,Sanofi S.A. | Beeske S.,Sanofi S.A. | Leroy T.,Sanofi S.A. | And 27 more authors.
Scientific Reports | Year: 2015

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.

Griebel G.,Exploratory Unit | Ravinet-Trillou C.,Infectious Diseases Therapeutic Strategic Unit | Beeske S.,Exploratory Unit | Avenet P.,Exploratory Unit | Pichat P.,Exploratory Unit
Frontiers in Endocrinology | Year: 2014

Disruption of circadian clock enhances the risk of metabolic syndrome, obesity, and type 2 diabetes. Circadian clocks rely on a highly regulated network of transcriptional and translational loops that drive clock-controlled gene expression. Among these transcribed clock genes are cryptochrome (CRY) family members, which comprise Cry1 and Cry2. While the metabolic effects of deletion of several core components of the clock gene machinery have been well characterized, those of selective inactivation of Cry1 or Cry2 genes have not been described. In this study, we demonstrate that ablation of Cry1, but not Cry2, prevents high-fat diet (HFD)-induced obesity in mice. Despite similar caloric intake, Cry1-/- mice on HFD gained markedly less weight (-18%) at the end of the 16-week experiment and displayed reduced fat accumulation compared to wild-type (WT) littermates (-61%), suggesting increased energy expenditure. Analysis of serum lipid and glucose profiles showed no difference between Cry1-/- and WT mice. Both Cry1-/- and Cry2-/- mice are indistinguishable from WT controls in body weight, fat and protein contents, and food consumption when they are allowed unlimited access to a standard rodent diet. We conclude that although CRY signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, Cry1 may play a role in readjusting energy balance under changing nutritional circumstances. These studies reinforce the important role of circadian clock genes in energy homeostasis and suggest that Cry1 is a plausible target for anti-obesity therapy. © 2014 Griebel, Ravinet-Trillou, Beeské, Avenet and Pichat.

Slowinski F.,Sanofi S.A. | Slowinski F.,Exploratory Unit | Ayad O.B.,Sanofi S.A. | Ayad O.B.,Exploratory Unit | And 6 more authors.
Organic Letters | Year: 2010

New azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives containing a pyridinyl substituent at the bridgehead position have been synthesized via an efficient ten chemical steps pathway. Both chemical series were then evaluated in vitro for their affinity at α7 nicotinic receptors revealing nanomolar potency with notably excellent selectivity over the α4β2 nicotinic subtype. © 2010 American Chemical Society.

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