N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo

Bisogno, Tiziana; Melck, Dominique; Bobrov, M. Yu.; Gretskaya, N. M.; Безуглов, В. В.; Petrocellis, Luciano De; Marzo, Vincenzo Di

doi:10.1042/0264-6021:3510817

Cited by 160 publications

(119 citation statements)

References 25 publications

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“…N -arachidonoyl-dopamine (NADA, 10 , Chart 2) is an endogenous “capsaicin-like” substance in mammalian nervous tissues. NADA activates cannabinoid CB1 receptors, but not dopamine Dl and D2 receptors [41, 42]. Virodhamine is arachidonic acid and ethanolamine joined by an ester linkage ( 11 , Chart 2).…”

Section: The Cannabinoid Receptorsmentioning

confidence: 99%

Endocannabinoid Binding to the Cannabinoid Receptors: What Is Known and What Remains Unknown

Reggio¹

2010

CMC

159

170

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The cannabinoid CB1 and CB2 receptors are Class A G protein-coupled receptors (GPCRs). While many Class A GPCRs have endogenous ligands that are hydrophilic cations (e.g., the serotonin and dopamine receptors), the cannabinoid receptors have neutral, highly lipophilic ligands derived from the fatty acid, arachidonic acid. The most well-studied of these are N-arachidonoylethanolamine (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). This review focuses on the experimental and computational studies that have been used to probe the nature of endocannabinoid interaction with the cannabinoid receptors. These studies include mutation, SAR and NMR studies, as well as, QSAR, docking and molecular dynamics simulations. Gaps in our knowledge are identified. The review begins more generally, however, by discussing the entire endocannabinoid system, of which the cannabinoid receptors are part. For in order to understand endocannabinoid action, one needs an appreciation for the environments for which these ligands have been designed and the conformational changes these ligands must undergo in order to act on the cannabinoid receptors.

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Section: The Cannabinoid Receptorsmentioning

confidence: 99%

Endocannabinoid Binding to the Cannabinoid Receptors: What Is Known and What Remains Unknown

Reggio¹

2010

CMC

159

170

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“…Until now, there are five recognized endocannabinoids, including 2-arachidonoyl glycerol (2-AG), arachidonoylethanolamine (anandamide), virodhamine, 14 2-arachidonyl glyceryl ether (noladin ether), and the recently discovered N -arachidonoyl-dopamine (NADA). 15 Many of these five ligands preferentially exhibit at the CB2 receptor. 2-Arachidonoyl glycerol (2-AG) selectively activates the pathway of MAPK-ERK.…”

Section: Introductionmentioning

confidence: 99%

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Feng

Alqarni

Yang

et al. 2014

J. Chem. Inf. Model.

100

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The cannabinoid receptor 2 (CB2) plays an important role in the immune system. Although a few of GPCRs crystallographic structures have been reported, it is still challenging to obtain functional transmembrane proteins and high resolution X-ray crystal structures, such as for the CB2 receptor. In the present work, we used 10 reported crystal structures of GPCRs which had high sequence identities with CB2 to construct homology-based comparative CB2 models. We applied these 10 models to perform a prescreen by using a training set consisting of 20 CB2 active compounds and 980 compounds randomly selected from the National Cancer Institute (NCI) database. We then utilized the known 170 cannabinoid receptor 1 (CB1) or CB2 selective compounds for further validation. Based on the docking results, we selected one CB2 model (constructed by β1AR) that was most consistent with the known experimental data, revealing that the defined binding pocket in our CB2 model was well-correlated with the training and testing data studies. Importantly, we identified a potential allosteric binding pocket adjacent to the orthosteric ligand-binding site, which is similar to the reported allosteric pocket for sodium ion Na+ in the A2AAR and the δ-opioid receptor. Our studies in correlation of our data with others suggested that sodium may reduce the binding affinities of endogenous agonists or its analogs to CB2. We performed a series of docking studies to compare the important residues in the binding pockets of CB2 with CB1, including antagonist, agonist, and our CB2 neutral compound (neutral antagonist) XIE35-1001. Then, we carried out 50 ns molecular dynamics (MD) simulations for the CB2 docked with SR144528 and CP55940, respectively. We found that the conformational changes of CB2 upon antagonist/agonist binding were congruent with recent reports of those for other GPCRs. Based on these results, we further examined one known residue, Val1133.32, and predicted two new residues, Phe183 in ECL2 and Phe2817.35, that were important for SR144528 and CP55940 binding to CB2. We then performed site-directed mutation experimental study for these residues and validated the predictions by radiometric binding affinity assay.

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“…In the present study, based on the involvement of TRPV1 receptors in the effects of CB1 ligands, the functional relationship between nAChRs and TRPV1 receptors [32], and the author's preliminary data on the antidepressant-like effects of some cannabimimetics against NC-induced depression-like behaviors [10], the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined against NC- and IM-induced depression-like behaviors in mice. Since few references on the depression-related behavioral alterations caused by TRPV1 ligands are available, the TRPV1 ligands were selected from those which provided some behavioral effects upon intraperitoneal or intravenous injections: the prototypic agonist capsaicin (CP) [33], the potent and antidepressant agonist olvanil (OL) [29], the antagonist capsazepine (CZ) [29], the endogenous TRPV1-agonistic CB1 agonists anandamide (arachidonylethanolamide: AEA) [27] and N-arachidonyldopamine (NADA) [34], as well as the synthetic TRPV1 and CB1 agonist arvanil (AR) [35]. …”

Section: Introductionmentioning

confidence: 99%

Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors

Hayase

2011

BMC Pharmacol

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BackgroundThe contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. In the present study, the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alterations in a mouse model in order to elucidate the "antidepressant-like" contributions of TRPV1 receptors against the NC-induced "depression" observed in various types of tobacco abuse.ResultsRepeated subcutaneous NC treatments (NC group: 0.3 mg/kg, 4 days), like repeated immobilization stress (IM) (IM group: 10 min, 4 days), caused depression-like behavioral alterations in both the forced swimming (reduced swimming behaviors) and the tail suspension (increased immobility times) tests, at the 2 h time point after the last treatment. In both NC and IM groups, the TRPV1 agonists capsaicin (CP) and olvanil (OL) administered intraperitoneally provided significant antidepressant-like attenuation against these behavioral alterations, whereas the TRPV1 antagonist capsazepine (CZ) did not attenuate any depression-like behaviors. Furthermore, the endogenous TRPV1-agonistic CB1 agonists anandamide (AEA) and N-arachidonyldopamine (NADA) did not have any antidepressant-like effects. Nevertheless, a synthetic "hybrid" agonist of CB1 and TRPV1 receptors, arvanil (AR), caused significant antidepressant-like effects. The antidepressant-like effects of CP and OL were antagonized by the TRPV1 antagonist CZ. However, the antidepressant-like effects of AR were not antagonized by either CZ or the CB1 antagonist AM 251 (AM).ConclusionsThe antidepressant-like effects of TRPV1 agonists shown in the present study suggest a characteristic involvement of TRPV1 receptors in NC-induced depression-like behaviors, similar to those caused by IM. The strong antidepressant-like effects of the potent TRPV1 plus CB1 agonist AR, which has been reported to cause part of its TRPV1-mimetic and cannabimimetic effects presumably via non-TRPV1 or non-CB1 mechanisms support a contribution from other sites of action which may play a therapeutically important role in the treatment of NC abuse.

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N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo

Cited by 160 publications

References 25 publications

Endocannabinoid Binding to the Cannabinoid Receptors: What Is Known and What Remains Unknown

Endocannabinoid Binding to the Cannabinoid Receptors: What Is Known and What Remains Unknown

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors

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