Therapeutic potential of targeting the endocannabinoids: Implications for the treatment of obesity, metabolic syndrome, drug abuse and smoking cessation

University of Liverpool, Eleanor Rathbone Building, Bedford Street South, Liverpool L69 7ZA, UK.
Current Medicinal Chemistry (Impact Factor: 3.72). 02/2006; 13(22):2669-80. DOI: 10.2174/092986706778201512
Source: PubMed

ABSTRACT Rimonabant (SR141716, Acomplia) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. It has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system. To date, data obtained from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have clinical benefits in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. Recently, it has been shown that rimonabant prevents indomethacin-induced intestinal injury by decreasing the levels of pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha), thus indicating that CB1 receptor antagonists might exhibit potential anti-inflammatory activity in acute and chronic diseases.

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    ABSTRACT: Cannabis has been used throughout the world for centuries. The psychoactive effects of cannabis are largely attributable to ∆9-tetrahydrocannabinol (∆9-THC), the prototypical cannabinoid that occurs naturally in the plant. More recently, chemically and pharmacologic-distinct synthetic cannabinoids (SCBs) have emerged as drugs of abuse. Compared with ∆9-THC, the distinct structures of these compounds allow them to avoid legal restrictions (at least initially) and detection in standard drug screens. This has contributed to the popularity of SCBs among drug users who seek to avoid positive drug screens. Importantly, the distinct structures of the SCBs also typically result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be responsible for the psychoactive effects of ∆9-THC and its analogues. Accordingly, it seems likely that these more powerful cannabimimetic effects could result in increased adverse reactions and toxicities not elicited by ∆9-THC in cannabis. Animal models useful for the study of emerging SCBs include the cannabinoid tetrad, drug discrimination, and assays of tolerance, dependence, and withdrawal. However, these in vivo procedures have not been particularly informative with regards to drug efficacy, where the majority of SCB effects are comparable with those of ∆9-THC. In contrast, essentially all in vitro measures of drug efficacy confirm ∆9-THC as a relatively weak CB1 partial agonist, whereas the majority of the SCBs detected in commercial preparations are full agonists at the CB1 receptor. As use of these emerging SCBs continues to rise, there is an urgent need to better understand the pharmacology and toxicology of these novel compounds.
    06/2014; 1(2). DOI:10.1007/s40429-014-0014-y
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    ABSTRACT: A set of 58 compounds of pyrimidines derivatives was subjected to molecular modeling studies using two-dimensional, k-Nearest Neighbor (kNN), and pharmacophore methods. Two-dimensional-QSAR modeling using simulated annealing or stepwise coupled partial least squares (SA-PLS and SW-PLS) methods identified some important topological indices, hydrophobic thermodynamic electronic and spatial descriptors properties descriptors as important factor for cannabinoid CB1 activity. The best quantitative structure–activity relationship models were further validated by leave-one-out method of cross-validation. The best 2D-QSAR model was selected, having showed best predictability of cannabinoid CB1 receptor activity with cross-validated value (q 2) = 0.7942, coefficient of determination (r 2) = 0.9054, and r 2_pred value of 0.8269 was developed by SA-PLS. kNN-MFA 3D QSAR was performed on the same series to correlate the effects of electrostatic, steric, and hydrophobic parameters with the cannabinoid CB1 activity using simulated annealing, stepwise forward backward regression and genetic algorithm methods. The best 3D model SA-PLS shows electrostatic descriptor present near R1 of the pyrimidine suggested that the electron-withdrawing group is required for enhancing the biological activity. The presence of steric descriptors with negative coefficients simultaneously at chloro and R2-positions of the pyrimidine ring, suggests the favorable of that less steric or less bulky substituents groups in these regions for producing potent cannabinoid CB1 receptor. Chemical feature-based pharmacophore models with lowest RMSD value (0.0681 Å), consists of two AroC feature (aromatic), one HDr (hydrogen-bond donor), one HAc (hydrogen-bond acceptor), and one (aliphatic) features was developed. This work may provide a platform for generating leads for novel cannabinoid CB1 receptor inhibitors.
    Medicinal Chemistry Research 05/2013; 23(5). DOI:10.1007/s00044-013-0808-9 · 1.61 Impact Factor
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