A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study

Proietto, Joseph; Rissanen, Aila; Harp, Joyce B.; Erondu, Ngozi; Yu, Qinfen; Suryawanshi, Shailaja; Jones, Mark; Johnson‐Levonas, Amy O.; Heymsfield, Steven B.; Kaufman, Keith D.; Amatruda, John M.

doi:10.1038/ijo.2010.38

Cited by 62 publications

(51 citation statements)

References 16 publications

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“…Decreased food intake in rodents and, to a lesser extent in humans, is accompanied by a robust reduction in body weight that is associated with an improved metabolic profile (Ravinet Trillou et al 2003;Gary-Bobo et al 2007;Janiak et al 2007;Van Gaal et al 2008). Together with similar clinical findings from a subsequent CB1 receptor inverse agonist, taranabant (Lin et al 2006;Aronne et al 2010;Proietto et al 2010;Wadden et al 2010), blockade of the CB1 receptor may thus be considered as a clinically well-validated target for production of modest but meaningful weight loss and reduced cardiovascular risk factors in obesity (Pi-Sunyer et al 2006;Van Gaal et al 2008;Wadden et al 2010). Some considerable debate, however, remains about the best way in which to target CB1 receptors for weight and metabolic control.…”

Section: F%mentioning

confidence: 83%

“…(n=4-6 per group) and Lutz 2008; Jacob et al 2009), and thus may be considered to have shown modest predictive validity for the anxiogenic findings in clinical studies with rimonabant. Sleep-wake EEG was chosen because alterations in sleepwake behavior have been previously reported for rimonabant in rats (Santucci et al 1996) and insomnia reported as an adverse event for both rimonabant (Pi-Sunyer et al 2006) and taranabant (Aronne et al 2010;Proietto et al 2010) and because sleep-wake EEG is considered a translatable paradigm (polysomnography).…”

Section: Discussionmentioning

confidence: 99%

“…However, CB1 receptors expressed in limbic and cortical regions likely mediate the well-known effects of antagonist/inverse agonists on emotion, learning, and memory (reviewed in Moreira and Lutz 2008;Thomas 2009). Indeed, in the clinic, both rimonabant and taranabant showed dose-related nausea and adverse psychological events such as depressive mood, anxiety, insomnia, and irritability (Aronne et al 2010;Pi-Sunyer et al 2006;Proietto et al 2010, Van Gaal et al 2008). These effects were present at weight-reducing doses; therefore, sufficient therapeutic windows were not attained and have been interpreted as mechanism-based (Aronne et al 2010).…”

Section: F%mentioning

confidence: 98%

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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

Jacobson

Commerford²,

Gerber³

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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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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Section: F%mentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: F%mentioning

confidence: 98%

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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

Jacobson

Commerford²,

Gerber³

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Chronic CP55,940-treated WT, but not CB 1 KO mice, showed profound withdrawal signs when challenged with the CB 1 antagonist rimonabant, suggesting precipitation at CB 1 receptors produces withdrawal symptoms (Tsou et al, 1995;Aceto et al, 1996;Cook et al, 1998;Rubino et al, 1998;Lichtman et al, 2001). Interestingly, although rimonabant challenge preferentially increased scratching bouts in mice treated with CP55,940 compared with vehicle, rimonabantelicited scratching was notably absent in CB 1 KO mice, demonstrating that antagonist-induced scratching [analogous to pruritis (Proietto et al, 2010)] in the absence of chronic cannabinoid dosing is mediated by CB 1 receptors, rather than an off-target effect of rimonabant. Our studies are the first to evaluate possible signs of physical dependence in animal pain models associated with repeated systemic activation of CB 2 receptors [present data and (Deng et al, 2015)].…”

mentioning

confidence: 99%

CB₁ Knockout Mice Unveil Sustained CB₂-Mediated Antiallodynic Effects of the Mixed CB₁/CB₂ Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

et al. 2015

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Cannabinoids suppress neuropathic pain through activation of cannabinoid CB 1 and/or CB 2 receptors; however, unwanted CB 1 -mediated cannabimimetic effects limit clinical use. We asked whether CP55,940 [(2)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexanol], a potent cannabinoid that binds with similar affinity to CB 1 and CB 2 in vitro, produces functionally separable CB 1 -and CB 2 -mediated pharmacological effects in vivo. We evaluated antiallodynic effects, possible tolerance, and cannabimimetic effects (e.g., hypothermia, catalepsy, CB 1 -dependent withdrawal signs) after systemic CP55,940 treatment in a mouse model of toxic neuropathy produced by a chemotherapeutic agent, paclitaxel. The contribution of CB 1 and CB 2 receptors to in vivo actions of CP55,940 was evaluated using CB 1 knockout (KO), CB 2 KO, and wild-type (WT) mice. Low-dose CP55,940 (0.3 mg/kg daily, i.p. ) suppressed paclitaxel-induced allodynia in WT and CB 2 KO mice, but not CB 1 KO mice. Low-dose CP55,940 also produced hypothermia and rimonabantprecipitated withdrawal in WT, but not CB 1 KO, mice. In WT mice, tolerance developed to CB 1 -mediated hypothermic effects of CP55,940 earlier than to antiallodynic effects. High-dose CP55,940 (10 mg/kg daily, i.p.) produced catalepsy in WT mice, which precluded determination of antiallodynic efficacy but produced sustained CB 2 -mediated suppression of paclitaxelinduced allodynia in CB 1 KO mice; these antiallodynic effects were blocked by the CB 2 antagonist 6-iodopravadoline (AM630). Highdose CP55,940 did not produce hypothermia or rimonabantprecipitated withdrawal in CB 1 KO mice. Our results using the mixed CB 1 /CB 2 agonist CP55,940 document that CB 1 and CB 2 receptor activations produce mechanistically distinct suppression of neuropathic pain. Our study highlights the therapeutic potential of targeting cannabinoid CB 2 receptors to bypass unwanted central effects associated with CB 1 receptor activation.

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“…The adverse effects reported, such as nausea and/or emesis and anhedonia or depression-related effects, are opposite to effects in humans commonly attributed to CB 1 agonists and, moreover, are not unique to rimonabant. Evidence that other CB 1 inverse agonists such as AM251 or taranabant have rimonabant-like profiles of action, including potential adverse effects, have similarly precluded their clinical application (Pertwee, 2005;Addy et al, 2008;Aronne et al, 2010;Proietto et al, 2010).…”

mentioning

confidence: 99%

Cannabinoid Discrimination and Antagonism by CB₁Neutral and Inverse Agonist Antagonists

Kangas¹,

Delatte²,

Vemuri³

et al. 2013

J Pharmacol Exp Ther

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Cannabinoid receptor 1 (CB 1 ) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB 1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB 1 inverse agonist SR141716A (rimonabant) and the CB 1 neutral antagonist AM4113 were compared for their ability to modify CB 1 receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB 1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB 1 discriminative stimulus, with an onset and time course of action comparable with that of the CB 1 agonist D 9 -tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA 2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB 1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB 1 receptors.

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A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study

Abstract: All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

Cited by 62 publications

References 16 publications

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

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

CB₁ Knockout Mice Unveil Sustained CB₂-Mediated Antiallodynic Effects of the Mixed CB₁/CB₂ Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

Cannabinoid Discrimination and Antagonism by CB₁Neutral and Inverse Agonist Antagonists

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A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study

Abstract: All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

Cited by 62 publications

References 16 publications

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

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

CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

Cannabinoid Discrimination and Antagonism by CB1Neutral and Inverse Agonist Antagonists

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About

CB₁ Knockout Mice Unveil Sustained CB₂-Mediated Antiallodynic Effects of the Mixed CB₁/CB₂ Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

Cannabinoid Discrimination and Antagonism by CB₁Neutral and Inverse Agonist Antagonists