Preferred conformations of endogenous cannabinoid ligand anandamide
| Autor: | Xiu-Wen Han, Jian-Zhong Chen, Xiang-Qun Xie |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Magnetic Resonance Spectroscopy
Cannabinoid receptor Polyunsaturated Alkamides Chemistry Stereochemistry Ligand medicine.medical_treatment Molecular Conformation Arachidonic Acids General Medicine Nuclear magnetic resonance spectroscopy Anandamide Ligands Endocannabinoid system General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Molecular dynamics Cannabinoid Receptor Modulators medicine lipids (amino acids peptides and proteins) Cannabinoid General Pharmacology Toxicology and Pharmaceutics Endocannabinoids G protein-coupled receptor |
| Zdroj: | Life Sciences. 76:2053-2069 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2004.08.041 |
| Popis: | Anandamide (arachidonyl-ethanolamide, AEA) is an important endogenous cannabinoid ligand isolated from porcine brain. AEA has a flexible molecular structure with a series of four non-conjugated double bonds, a hydrophobic alkyl chain, and a carboxyamide head group. It is known that AEA binds to cannabinoid receptor and induces cannabimimetic activity. However, questions still remain about the three-dimensional arrangement of the pharmacophoric groups of AEA that facilitate its interaction with cannabinoid receptor, a member of transmembrane G-protein coupled receptors (GPCRs). Such information is of critical importance for the design of novel analogs of potential therapeutic values. In the present studies, we developed a combined approach of 2D high-resolution NMR and computer modeling to investigate conformational features of AEA in solution. The developed method and experimental data is then applied to study the structural properties of AEA in a membrane-like environment that will be reported elsewhere. In addition to the measured NOEs, the dihedral angle constraints were for the first time being used as experimentally-determined structural constraints for performing molecular dynamics simulations to refine the NMR-determined AEA conformations. Our results showed that AEA prefers an extended pseudo-helical conformation in solution with two oxygen atoms pointing towards the same side and a straight pentyl chain, which was an averaged conformation observed on the basis of NMR time scale. The results were correlated to the computer predicted AEA models reported by others. The established NMR-based computational approach provides an alternative way to explore further the detailed conformational properties of AEA that encodes important pharmacophoric and conformational information regarding the activation of cannabinoid receptors. |
| Databáze: | OpenAIRE |
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