Cannabinoid CB2/CB1 Selectivity. Receptor Modeling and Automated Docking Analysis

Abstract

Three-dimensional models of the CB1 and CB2 cannabinoid receptors were constructed by means of a molecular modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template, and taking into account the available site-directed mutagenesis data. The cannabinoid system was studied by means of docking techniques. An analysis of the interaction of WIN55212-2 with both receptors showed that CB2/CB1 selectivity is mainly determined by the interaction in the CB2 with the nonconserved residues S3.31 and F5.46, whose importance was suggested by site-directed mutagenesis data. We also carried out an automated docking of several ligands into the CB2 model, using the AUTODOCK 3.0 program; the good correlation obtained between the estimated free energy binding and the experimental binding data confirmed our binding hypothesis and the reliability of the model.

Ligand-specific homology modeling of human cannabinoid (CB1) receptor

“…In our model, ACEA binds to TMH2-3-6-7 region and adopted a folded J-shape to form hydrophobic intermolecular contacts with CB1 receptor. U-shaped endocannabinoids conformations were also found in others studies [11,16]. ACEA is located at the lipophilic region of the binding site and in the vicinity of residues such as K3.…”

“…Up to late 2007, the CB1 receptor model was built based on bovine rhodopsin, a GPCR, because of its available high-resolution structure as a template for CB1 receptor modeling [10,11,[13][14][15][16]. In recent years, with more GPCR structures being crystallized, new templates such as human adenosine A 2A receptor (AA 2A R) and ␤ 2 adrenergic receptor (␤ 2 AR) have become available [12,17,18].…”

Standardized Cannabis and Pain Management

“…CB2 receptors are found mostly in peripheral immune tissues such as the spleen, tonsils and thymus glands where they're primarily localized on immune cells such as monocytes, macrophages, B-cells, and T-cells. [17][18][19][20] Reducing intracellular levels of cyclic adenosine monophosphate (cAMP), leads to a series of down-regulatory events ultimately resulting in lowered immunity. Other types of cannabinoid receptors (CB3) are proposed and will undoubtedly more will emerge as research continues.…”

A chemometric study on the analgesic activity of cannabinoid compounds using SDA, KNN and SIMCA methods

“…About 41 years ago, Gaoni and Mechoulam identified D 9 -tetrahydrocannabinol (THC) as the main psychoactive molecule present in Cannabis sativa [3]. The pharmacological effects of cannabinoids are mediated through at least two receptors, named as CB 1 and CB 2 , and these effects include tachycardia, hypothermia, analgesia, and the appetite-enhancing effects [3,4].…”

“…The pharmacological effects of cannabinoids are mediated through at least two receptors, named as CB 1 and CB 2 , and these effects include tachycardia, hypothermia, analgesia, and the appetite-enhancing effects [3,4]. In this work, we have studied cannabinoid compounds with analgesic activity and this is significant since the control of pain requires a knowledge of the pain mechanisms and an understanding of the drugs used for this purpose.…”