Homology model of the CB1 cannabinoid receptor: Sites critical for nonclassical cannabinoid agonist interaction

  title={Homology model of the CB1 cannabinoid receptor: Sites critical for nonclassical cannabinoid agonist interaction},
  author={Joong-Youn Shim and William J. Welsh and Allyn C. Howlett},
  journal={Peptide Science},
Association of cannabimimetic compounds such as cannabinoids, aminoalkylindoles (AAIs), and arachidonylethanolamide (anandamide) with the brain cannabinoid (CB1) receptor activates G‐proteins and relays signals to regulate neuronal functions. A CB1 receptor homology model was constructed using the published x‐ray crystal structure of bovine rhodopsin (Palczewski et al., Science, 2000 , Vol. 289, pp. 739–745) in the conformation most likely to represent the “high‐affinity” state for agonist… 

Binding mode prediction of conformationally restricted anandamide analogs within the CB1 receptor

To better understand the molecular interactions associated with binding and steric trigger mechanisms of receptor activation, a series of conformationally-restricted anandamide analogs having a wide range of affinity and efficacy were evaluated.

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

Negative allosteric modulators of cannabinoid receptor 1: Ternary complexes including CB1, orthosteric CP55940 and allosteric ORG27569

The studies show that the computational techniques used are valuable in identifying ligand-binding pockets in proteins, and could be useful for the study of the interaction mode of other allosteric modulators.

Steric Trigger as a Mechanism for CB1 Cannabinoid Receptor Activation

It was shown from the present MD simulations that the torsion angles phi1 and phi4 of the C3 side chain showed the most dramatic change when compared with the ground-state receptor-bound conformation, indicating thatrotational flexibility in a ligand may be as important a determinant of agonist activity as the pharmacophile elements that can be identified.

Understanding Functional Residues of the Cannabinoid CB1 Receptor for Drug Discovery

The early stages of the CB(1) receptor activation process are proposed that provide some insights into understanding molecular mechanisms of receptor activation but also are applicable for identifying new therapeutic agents by applying the validated structure-based approaches, such as virtual high throughput screening (HTS) and fragment-based approach (FBA).

Toward the design of cannabinoid CB1 receptor inverse agonists and neutral antagonists

The combined mutation and modeling studies that have led to the identification of interactions key to the inverse agonism of SR141716A are presented and the development of the first CB1 neutral antagonists based on these modeling/mutation results is discussed.

Dual Role of the Second Extracellular Loop of the Cannabinoid Receptor 1: Ligand Binding and Receptor Localization

The findings are consistent with a dual role for EC2 in stabilizing receptor assembly and in ligand binding and revealed that highly hydrophobic residues are required to accomplish both functions.

A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: homology modeling, docking, de novo drug design and molecular dynamics analysis

Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands.

The application of 3D-QSAR studies for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements for binding to cannabinoid receptors CB1 and CB2.

The CoMFA and CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptors allowed us to deduce the possible optimal binding positions and this information can be used for the design of new CB analogues with enhanced activity and other tailored properties.



Ligand Binding and Modulation of Cyclic AMP Levels Depend on the Chemical Nature of Residue 192 of the Human Cannabinoid Receptor 1

The results of this study indicate that binding of CP‐55,940 is highly sensitive to the chemical nature of residue 192, and suggests a role for Lys192 in WIN 55,212‐2‐induced receptor activation.

A lysine residue of the cannabinoid receptor is critical for receptor recognition by several agonists but not WIN55212-2.

Results demonstrate that Lys192 is critical for receptor binding by HU-210, CP-55940, and anandamide, and that WIN55212-2 must interact with the cannabinoid receptor through at least one point of interaction that is distinct from those of the three other agonists.

Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs.

Several series of CP-47,497 analogs are examined for their binding affinity at the cannabinoid receptor and their ability to evoke analgesia in rodents and in general, analgesic activity correlated well with the affinity of these analogs for the cannabinoids receptor.

Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity.

It is found that a high-affinity site for (-)-3-[2-hydroxyl-4-(1, 1-dimethylheptyl)phenyl]-4-[3-Hydroxyl propyl] cyclohexan-1-ol (CP-55,940) in the region of helices 3, 6, and 7 is identified, which could lead to subtype specificity.

Structure-activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity.

This study demonstrates that the potency could be optimized in (-)-CP-55,244 for both binding to the CB1 receptor and the biological activity of analgesia, and defines the critical stereochemistry for a region of the nonclassical ACD-tricyclic cannabinoid structure that contributes a potential hydrogen bonding component to the ligand-receptor interaction mechanism.

The CB1Cannabinoid Receptor in the Brain

  • A. Howlett
  • Biology, Chemistry
    Neurobiology of Disease
  • 1998
It is proposed that conformational changes in the receptor induced by agonist ligands may alter the conformation or exposure of the juxtamembrane C-terminal region extending from helix VII.

The Conformational Properties of the Highly Selective Cannabinoid Receptor Ligand CP-55,940 (*)

This work has studied the conformational properties of CP-55,940 using a combination of solution NMR and computer modeling methods to obtain information on the stereoelectronic requirements at the cannabinoid receptor active site.

Structural Features of the Central Cannabinoid CB1 Receptor Involved in the Binding of the Specific CB1 Antagonist SR 141716A (*)

From binding experiments with mutated CB1 and with chimeric CB1/CB2 receptors the authors have begun to identify the domains of CB1 implicated in the recognition of SR 141716A, a high specificity for the central CB1 cannabinoid receptor and negligeable affinity for the peripheral CB2 receptor.

The cannabinoid receptor: computer-aided molecular modeling and docking of ligand.

  • M. Mahmoudian
  • Biology, Chemistry
    Journal of molecular graphics & modelling
  • 1997

Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model.

It is postulated that the receptor that is associated with the regulation of adenylate cyclase in vitro may be the same receptor as that mediating analgesia in vivo, and a conceptualization of the cannabinoid analgetic receptor is presented.