Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Fong, Tung M.; Heymsfield, S B

doi:10.1038/ijo.2009.132

Cited by 94 publications

(62 citation statements)

References 70 publications

(79 reference statements)

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“…These heterocyclic systems are found in a number of molecules possessing biological and pharmacological activities such as antimicrobial (Raviraj et al, 2013), anti-inflammatory (Fong & Heymsfield, 2009) and antiviral (Bernardino et al, 2007). Besides their pharmacological properties, pyrazolo [3,4-b]pyridines also exhibit corrosion inhibition properties (Gupta et al, 2015).…”

Section: Structure Descriptionmentioning

confidence: 99%

Ethyl 4,6-dimethyl-3-oxo-2-phenyl-3,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate monohydrate

et al. 2016

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In the title compound, C 17 H 17 N 3 O 3 ÁH 2 O, the dihedral angle between the 4,6-dimethyl-pyrazolo [3,4-b]pyridine-3-one unit [maximum deviation = 0.048 (2) Å ] and the phenyl ring is 5.1 (1) . The structure is characterized by disorder of the carboxylate O atoms, which are split into two parts with a major component of 0.898 (4). In the crystal, the organic molecules and lattice water molecules are linked via O-HÁ Á ÁO, O-HÁ Á ÁN and N-HÁ Á ÁO hydrogen bonds. The molecules are also linked by C-HÁ Á Á and weak offset -stacking interactions, forming sheets parallel to (001). Structure descriptionThe number of substituted pyrazolo [3,4-b]pyridines has increased in organic and pharmaceutical chemistry. These heterocyclic systems are found in a number of molecules possessing biological and pharmacological activities such as antimicrobial (Raviraj et al., 2013), anti-inflammatory (Fong &Heymsfield, 2009) and antiviral (Bernardino et al., 2007). Besides their pharmacological properties, pyrazolo [3,4-b]pyridines also exhibit corrosion inhibition properties (Gupta et al., 2015). As part of our research on the preparation of new pyrazolo [3,4-b]pyridine-3-ones (Fadel et al., 2011), the title compound was isolated and its crystal structure was determined by X-ray diffraction.The molecular structure is shown in Fig. 1. The dihedral angle between the 4,6-dimethyl-pyrazolo[3,4-b]pyridine-3-one unit [maximum deviation = 0.048 (2) Å ] and the phenyl ring is 5.1 (1) . In the crystal, the components are linked through O-HÁ Á ÁO, O-

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Section: Structure Descriptionmentioning

confidence: 99%

Ethyl 4,6-dimethyl-3-oxo-2-phenyl-3,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate monohydrate

et al. 2016

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“…Another example where increased drug exposure may lead to a similar time-response pattern is the observed body weight suppression after CB 1 -receptor antagonists. Such agents are anorexigenic but will also at higher exposure increase energy expenditure and thereby increase the burning of body fat, both processes in turn contributing to body weight loss (17).…”

Section: Case Studymentioning

confidence: 99%

Pattern Recognition in Pharmacodynamic Data Analysis

Gabrielsson

Stephan

2015

AAPS J

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Abstract. Pattern recognition is a key element in pharmacodynamic analyses as a first step to identify drug action and selection of a pharmacodynamic model. The essence of this process is going from data to insight through exploratory data analysis. There are few formal strategies that scientists typically use when the experiment has been done and data collected. This report attempts to ameliorate this deficit by identifying the properties of a pharmacodynamic model via dissection of the pattern revealed in responsetime data. Pattern recognition in pharmacodynamic analyses contrasts with pharmacokinetic analyses with respect to time course. Thus, the time course of drug in plasma usually differs markedly from the time course of the biomarker response, as a consequence of a myriad of interactions (transport to biophase, binding to target, activation of target and downstream mediators, physiological response, cascade and amplification of biosignals, homeostatic feedback) between the events of exposure to test compound and the occurrence of the biomarker response. Homing in on this important-but less often addressed-element, 20 datasets of varying complexity were analyzed, and from this, we summarize a set of points to consider, specifically addressing baseline behavior, number of phases in the response-time course, time delays between concentration-and response-time courses, peak shifts in response with increasing doses, saturation, and other potential nonlinearities. These strategies will hopefully give a better understanding of the complete pharmacodynamic response-time profile.

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“…Hence, to circumvent the problems that have beset the current agents, some strategies such as developing non-brain penetrating and peripheral restrictive CB 1 receptor antagonists or focusing on allosteric modulation of CB 1 receptors are being used at present [7,8] . Previously reported cannabinoid CB 1 receptor selective antagonists exhibited mainly two types of behavior [9,10] . One type, expressed by SR141716A and Imidazole 24b, has effects in the opposite direction to those produced by the cannabinoid receptor agonists, ie, they are cannabinoid CB 1 receptor inverse agonists [11,12] .…”

Section: Introductionmentioning

confidence: 99%

Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Chen¹,

Liu³

et al. 2011

Acta Pharmacol Sin

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Aim: To characterize the biological profiles of MJ08, a novel selective CB 1 receptor antagonist. Methods: Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB 1 and CB 2 receptor redistribution and intracellular Ca 2+ ([Ca 2+ ] i ) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice. Results: In radioligand binding assay, MJ08 selectively antagonized CB 1 receptor (IC 50 =99.9 nmol/L). In EGFP-CB 1 _U2OS cells, its IC 50 value against CB 1 receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca 2+ ] i in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB 1 cells. MJ08 (10 nmol/L-10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA 2 =10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB 1 cells with an EC 50 value of 78.6 nmol/L, which was lower than the EC 50 value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB 1 receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo. Conclusion: MJ08 is a novel, potent and selective CB 1 receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB 1 receptors.

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Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Cited by 94 publications

References 70 publications

Ethyl 4,6-dimethyl-3-oxo-2-phenyl-3,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate monohydrate

Ethyl 4,6-dimethyl-3-oxo-2-phenyl-3,7-dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate monohydrate

Pattern Recognition in Pharmacodynamic Data Analysis

Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

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