3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB1) Receptor Antagonist Rimonabant: Cannabinoid Agonist-Like Effects in Mice via Non-CB1, Non-CB2 Mechanism

Wiley, Jenny L.; Selley, Dana E.; Wang, Pinglang; Kottani, Rudresha; Gadthula, Srinivas; Mahadeven, Anu

doi:10.1124/jpet.111.187815

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…Rimonabant is relatively selective for cannabinoid CB 1 receptors (Rinaldi-Carmona et al, 1994), but also binds to alpha 2 -adrenergic and μ opioid receptors; the latter is suggested to mediate the inverse agonism obtained at relatively large concentrations of rimonabant in vitro (Cinar and Scucz, 2009; Pertwee et al, 2010). The cannabinoid agonists included for study are relatively non-selective for cannabinoid CB 1 and CB 2 receptors and some of the agonists appear to produce behavioral effects through non-cannabinoid CB 1 and non-CB 2 receptor mechanisms (Wiley et al, 2012), with GPR55 identified as a potential site of action for Δ 9 -THC in particular. Relatively large doses of rimonabant decrease operant response rate (McMahon, 2011), potentially through actions at non-cannabinoid CB 1 receptors, which in turn could yield less orderly antagonism than that of other effects mediated solely by cannabinoid CB 1 receptors.…”

Section: Discussionmentioning

confidence: 99%

JWH-018 in rhesus monkeys: Differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

Rodriguez¹,

McMahon²

2014

European Journal of Pharmacology

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SUMMARY Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50 = 0.01 mg/kg) and decreased response rate (ED50 = 0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940 = JWH-018 > Δ9-THC = WIN-55212-2 = JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and 9-THC decreased rectal temperature by 2.2 and 2.8 °C, respectively; the doses decreasing temperature by 2 °C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and 9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoid on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.

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Section: Discussionmentioning

confidence: 99%

JWH-018 in rhesus monkeys: Differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

Rodriguez¹,

McMahon²

2014

European Journal of Pharmacology

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“…O-6629 is one of a series of rimonabant analogs in which various substituents have been substituted for the 3-substituent of its pyrazole core. Unlike rimonabant, however, this set of analogs produces a battery of in vivo cannabinoid effects in inbred and CB 1 knockout mice [121]. In addition, their potencies in these tests are not strongly correlated with their binding affinities for the CB 1 receptor.…”

Section: Cannabinoid Antagonist Discriminationmentioning

confidence: 98%

Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids

Wiley

Owens

Lichtman

2016

The Behavioral Neuroscience of Drug Discrimination

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Psychoactive cannabinoids from the marijuana plant (phytocannabinoids), from the body (endocannabinoids), and from the research lab (synthetic cannabinoids) produce their discriminative stimulus effects by stimulation of CB receptors in the brain. Early discrimination work with phytocannabinoids confirmed that Δ-tetrahydrocannabinol (Δ-THC) is the primary psychoactive constituent of the marijuana plant, with more recent work focusing on characterization of the contribution of the major endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), to Δ-THC-like internal states. Collectively, these latter studies suggest that endogenous increases in both anandamide and 2-AG seem to be optimal for mimicking Δ-THC's discriminative stimulus effects, although suprathreshold concentrations of anandamide also appear to be Δ-THC-like in discrimination assays. Recently, increased abuse of synthetic cannabinoids (e.g., "fake marijuana") has spurred discrimination studies to inform regulatory authorities by predicting which of the many synthetic compounds on the illicit market are most likely to share Δ-THC's abuse liability. In the absence of a reliable model of cannabinoid self-administration (specifically, Δ-THC self-administration), cannabinoid discrimination represents the most validated and pharmacologically selective animal model of an abuse-related property of cannabinoids - i.e., marijuana's subjective effects. The influx of recent papers in which cannabinoid discrimination is highlighted attests to its continued relevance as a valuable method for scientific study of cannabinoid use and abuse.

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“…for tetrad) prevent absolute comparison of dose effects across procedure, it is nonetheless likely that these decreases in food intake were related to suppression of locomotor activity rather than to a specific anorexic effect, as all three analogs produced agonist-like effects in the tetrad tests (including hypomobility) at doses that were 3- to 18-fold lower. Previous work with these and similar 3-substituted pyrazoles demonstated conclusively that the cannabinoid agonist-like effects of this class of analogs were not cannabinoid CB 1 receptor-mediated, despite the excellent cannabinoid CB 1 receptor binding affinities possessed by some (but not all) of the analogs (Wiley et al, 2012). In contrast, in a series of pyrazole analogs with substitutions at the 3-position, Compound 31 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- N -(1-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-cyclopropyl)-1H-pyrazole-3-carboxamide] showed good cannabinoid CB 1 receptor affinity, antagonized the hypothermic effects of WIN55,212-2, and decreased feeding in mice following acute adminstration as well as in a mouse model of diet-induced obesity (Sasmal et al, 2011).…”

Section: Discussionmentioning

confidence: 85%

Structural analogs of pyrazole and sulfonamide cannabinoids: Effects on acute food intake in mice

Wiley¹,

Marusich²,

Zhang³

et al. 2012

European Journal of Pharmacology

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Obesity contributes to a multitude of serious health problems. Given the demonstrated role of the endogenous cannabinoid system in appetite regulation, the purpose of the present study was to evaluate structural analogs of two cannabinoids, rimonabant (cannabinoid CB1 receptor antagonist) and O-2050 (sulfonamide analog of Δ8-tetrahydrocannabinol), that showed appetite suppressant effects in previous studies. Structure–activity relationships of these two lead compounds were examined in several assays, including cannabinoid CB1 and CB2 receptor binding, food intake, and an in vivo test battery (locomotor activity, antinociception, ring immobility, and body temperature) in mice. Rimonabant and O-2050 reliably decreased feeding in mice; however, their analogs decreased feeding only at higher doses, even though some compounds had quite good cannabinoid CB1 binding affinity. Results of the in vivo test battery were inconsistent, with some of the compounds producing effects characteristic of cannabinoid agonists while other compounds were inactive or were antagonists against an active dose of Δ9-tetrahydrocannabinol. These results demonstrate that reduction of food intake is not a characteristic effect of pyrazole and sulfonamide cannabinoid analogs with favorable cannabinoid CB1 binding affinity, suggesting that development of these classes of cannabinoids for the treatment of obesity will require evaluation of their effects in a broad spectrum of pharmacological assays.

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3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB₁) Receptor Antagonist Rimonabant: Cannabinoid Agonist-Like Effects in Mice via Non-CB₁, Non-CB₂ Mechanism

Cited by 16 publications

References 31 publications

JWH-018 in rhesus monkeys: Differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

JWH-018 in rhesus monkeys: Differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids

Structural analogs of pyrazole and sulfonamide cannabinoids: Effects on acute food intake in mice

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