title: 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.
abstract: A set of 30 novel Delta8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensional quantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination of molecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the most potent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the template and CB1 and CB2 pharmacophore models were developed. These models were fitted with experimental binding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFA and CoMSIA approaches show that steric effects dominantly determine the binding affinities. 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. This information can be used for the design of new CB analogues with enhanced activity and other tailored properties.
authors.affiliation: Institute of Organic and Pharmaceutical Chemistry, The National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, 11635 Athens, Greece.
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.forename: Agnes
authors.initials: A
authors.lastname: Kapou
authors.forename: Therapia
authors.initials: T
authors.lastname: Kourouli
authors.forename: Thanos
authors.initials: T
authors.lastname: Andreou
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Nahmias
authors.forename: Demetris P
authors.initials: DP
authors.lastname: Papahatjis
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D004220:Disulfides / Q000737:chemistry; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000737:chemistry*; D016018:Least-Squares Analysis; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry*; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry*
chemical_list: D004220:Disulfides; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol