Novel benzimidazole derivatives as selective CB2 agonists

Pagé, Daniel; Balaux, Elise; Boisvert, Luc; Liu, Ziping; Milburn, Claire; Tremblay, Maxime; Wei, Zhongyong; Woo, Simon; Luo, Xi; Cheng, Yun‐Xing; Yang, Hua; Srivastava, Sanjay K.; Zhou, Fei; Brown, W. A.; Tomaszewski, Mirosław J.; Walpole, Christopher; Hodzic, Leila; St-Onge, Stéphane; Godbout, Claude; Salois, Dominic; Payza, Keymal

doi:10.1016/j.bmcl.2008.05.073

Cited by 61 publications

(34 citation statements)

References 43 publications

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“…Structure-activity relationships for synthetic cannabinoids have been established [4][5][6][7][8], and JWH compounds (JWH-018, JWH-122, and JWH-073) have been modified as follows: introduction of a fluorine atom (AM-2201, MAM-2201, and EAM-2201) [9] and substitution of the naphthyl group for a cyclopropyl group (UR-144 and XLR-11) [10,11], adamantyl group (APICA and 5F-APICA) [10], or quinolinyl group (QUPIC and QUCHIC) [12,13]. Synthetic cannabinoids have been found in seized herbal materials, and their continual emergence on recreational and illicit drug markets has become a global issue [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

et al. 2016

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MAM-2201 is a synthetic cannabinoid that is increasingly found in recreational drug abusers and cases of severe intoxication. Thus, characterization of the metabolic pathways of MAM-2201 is necessary to predict individual pharmacokinetics and toxicity differences, and to avoid toxic drug-drug interactions. Collectively, 19 phase 1 metabolites of MAM-2201 were identified using liquid chromatography-Orbitrap mass spectrometry following human liver microsomal incubations in the presence of NADPH: 7 hydroxy-MAM-2201 (M1-M7), 4 dihydroxy-MAM-2201 (M8-M11), dihydrodiol-MAM-2201 (M12), N-(5-hydroxypentyl)-MAM-2201 (M13), hydroxy-M13 (M14), N-dealkyl-MAM-2201 (M15), 2 hydroxy-M15 (M16, M17), MAM-2201 N-pentanoic acid (M18), and hydroxy-M18 (M19). On the basis of intrinsic clearance values in human liver microsomes, hydroxy-MAM-2201 (M1), N-(5-hydroxypentyl)-MAM-2201 (M13), and hydroxy-M13 (M14) were the major metabolites. Based on an enzyme kinetics study using human cDNA-expressed cytochrome P450 (CYP) enzymes and an immunoinhibition study using selective CYP antibodies in human liver microsomes, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were responsible for MAM-2201 metabolism. The CYP3A4 enzyme played a prominent role in MAM-2201 metabolism, and CYP1A2, CYP2B6, CYP2C8, and CYP2C9 enzymes played major roles in the formation of some metabolites. MAM-2201 is extensively metabolized by multiple CYP enzymes, indicating that MAM-2201 and its metabolites should be used as markers of MAM-2201 abuse and toxicity. Graphical abstract In vitro metabolic pathways of MAM-2201 were characterized in human liver microsomes and recombinant CYPs using LC-HRMS analysis. Total 19 phase I metabolites were identified with predominant contribution of CYP3A4.

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Section: Introductionmentioning

confidence: 99%

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

et al. 2016

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“…A dataset of twenty-seven 1,2,3,4-tetrahydropyrrolo [3,4-b]indole derivatives ( Table 1, compounds 1-27) and thirty-six benzimidazole derivatives ( Table 2, compounds 28-63), screened according to the same pharmacological protocol, were selected from literature [22,23]. All the compounds have been built, parameterized (Gasteiger-Hückel method) and energy minimized within MOE using MMFF94 forcefield [24].…”

Section: Data Setmentioning

confidence: 99%

“…Recently, novel classes of CB2 agonists based on 1,2,3,4-tetrahydropyrrolo [3,4-b]indole and benzimidazole scaffolds [22,23] (in Fig. 1, representative compounds 8 and 31 are depicted) have shown high binding affinity toward CB2 receptor and good selectivity over CB1 receptor.…”

Section: Introductionmentioning

confidence: 99%

CoMFA and CoMSIA analyses on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole derivatives as selective CB2 receptor agonists

et al. 2010

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Novel classes of cannabinoid 2 receptor (CB2) agonists based on 1,2,3,4tetrahydropyrrolo[3,4-b]indole and benzimidazole scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over cannabinoid 1 receptor (CB1). A computational study of Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) was performed, initially on each series of agonists, and subsequently on all compounds together, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing cross-validated r2 (rcv2) = 0.680, non cross-validated r2 (rncv2) = 0.97 and test set r2 (r2pred) = 0.93. The study provides useful suggestions for the design of new analogues with improved affinity. Response to Reviewers: In this manuscript, CoMFA and CoMSIA analyses were performed as suggested by reviewer#1. Thus, to derive the final CoMFA and CoMSIA models, 44 compounds were assigned to the training set, for model generation, and 19 ligands to the test set, for model validation. The test set molecules represent the 30% of the training set and cover 4 log orders of magnitude.

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“…Benzo[d]imidazole derivatives Other CB2 agonists based on benzo[d]imidazole template have been reported by AstraZeneca from HTS studies. SAR studies around benzo[d]imidazole derivatives modifying the N-1 position with alkyl and aromatic groups led to the 1-cyclopropylmethyl derivative 23 with optimal potency and selectivity[153]. sulphonyl group at the 5 position led to one of the best compounds of these series, the 5-sulphonyl tetrahydorbenzo[d]imidazole 24,(Table 1,…”

mentioning

confidence: 99%

Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

Páez

Campillo

2019

CMC

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The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

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Novel benzimidazole derivatives as selective CB2 agonists

Cited by 61 publications

References 43 publications

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes

CoMFA and CoMSIA analyses on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole derivatives as selective CB2 receptor agonists

Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

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