Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents

Abstract

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.

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…Interestingly, compound 157-induced analgesic effects can be reversed by a CB1 (131) but not a CB2 (1) antagonist, which indicated that 157 mainly produced analgesia through a CB1-dependent mechanism. 169 Although the administration of 157 was demonstrated to be devoid of inducing hypothermia, catalepsy, and hypomotility, it resulted in an alteration of learning and memory performance. This adverse property might limit the application of 157 in a clinical setting.…”

“…This adverse property might limit the application of 157 in a clinical setting. 169 The investigation of its binding mechanism indicated that the Ser132 of MAGL could interact with the carbamate moiety of 157 accompanied by the release of hexafluoropropyloxy group. The carbonyl oxygen of the carbamate moiety was suggested to serve as an H-bond acceptor and bind to Ala61/Met133.…”

“…165 In Most recently, a novel potent and selective MAGL inhibitor, compound 157 (SAR127303, Figure 55), was revealed to inactivate MAGL at nanomolar levels (IC50 (mMAGL) = 3.8 nM), markedly elevate 2-AG levels in mice and produce analgesic effects in several models of inflammation and pain. 169 Notably, compound 157 displayed high selectivity over most human serine enzymes except ABHD6 and was devoid of effects on 170 kinases, ion channels, transporters, and cannabinoid receptors, including CB1…”

“…One oxygen atom of the sulfonyl moiety was found to interact with the main chain of Asn162 through the formation of H-bond as well as additionally make contact with the side chain of Asn162 and the main chain of Leu251 through water-mediated interactions ( Figure 57). 169 Like most O-hexafluoropropyloxy carbamates, the hexafluoropropyloxy moiety of 157 served as the leaving group during catalysis. 169 Furthermore, [ 11 C]-157 has been synthesized as a radiotracer for investigating the density and distribution of MAGL, which could be used for the diagnosis of CNSdependent disorders (such as nerve injury).…”

“…In addition, compound 157-induced activity was detectable until 24 h post-dose. 169 Compound 157 elicited anti-nociceptive activities in several models of pain and inflammation (such as phenylbenzoquinone (PBQ)-induced writhing, 3 mg/kg oral dose).…”