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.

Modulation of food consumption and sleep–wake cycle in mice by the neutral CB1 antagonist ABD459

“…Here, alterations in spectral power, which were observed throughout the recording period and appeared independent of washout, mainly occurred in the hippocampus and presented as a lowering of delta power during NREM sleep and wakefulness and as an increase in spectral power of theta activity during wakefulness. Such a lowering of spectral power has also been reported during NREM sleep for rimonabant (Santucci et al , 1996) and compound 64 (Jacobson et al , 2011) in rats. However, the fact that rimonabant was not efficient during wakefulness may yet again point towards different pharmacological properties compared with AM251.…”

“…What the CB 1 -independent component reflects is unclear at present, but the strong suppression of REM sleep may be because of a lowering of the cholinergic tone after WIN-2, an action that is consistent with behavioural data (Goonawardena et al , 2010a; Robinson et al , 2010) and also with the notion that REM sleep is dependent on high cholinergic activity (Platt and Riedel, 2011 for review). By contrast, REM sleep reductions observed after AM251, compound 64 and ABD459 treatment are unlikely to be explained by cholinergic mechanisms, but may reflect genuine inhibition of CB 1 -dependent modulation of GABAergic activity in sleep-relevant brain centres such as the lateral hypothalamus and brainstem (Saper et al , 2001; Gottesmann, 2002; Blanco-Centurion et al , 2006; Jacobson et al , 2011). …”

Endocannabinoid Signaling Regulates Sleep Stability

“…Studies in CB1 KO mice have found significantly reduced NREM bout duration with an increased number of NREM bouts [ 24 , 25 ]. REM sleep is consistently reduced following administration of CB1 antagonists [ 28 , 29 , 32 , 79 , 80 ], and reduced REM sleep is frequently associated with NREM fragmentation [ 67 , 68 ]. In the present study, reductions in REM sleep time were associated with time points where there was noticeable fragmentation of NREM.…”

Sex differences in mouse models of fear inhibition: Fear extinction, safety learning, and fear–safety discrimination

“…Two paradigms of fear conditioning were employed with differing levels of footshock intensity ( n = 10 male and n = 10 female mice per paradigm; Jacobson et al, ). On Day 1, mice were habituated to Experimental Context A for 2 min before presentation of five tone stimuli (CS+; 5 kHz, 80 dB, 10 s; inter‐trial interval [ITI] = 60 s) which co‐terminated with a footshock (moderate paradigm: 0.6 mA, 1 s; intense paradigm: 0.8 mA, 2 s).…”