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
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- 作者：Serdar Durdagi ; Agnes Kapou ; Therapia Kourouli ; Thanos Andreou ; Spyros P. Nikas ; Victoria R. Nahmias ; Demetris P. Papahatjis ; Manthos G. Papadopoulos ; Thomas Mavromoustakos
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：June 14, 2007
- 年：2007
- 卷：50
- 期：12
- 页码：2875 - 2885
- 全文大小：462K
- 年卷期：v.50,no.12(June 14, 2007)
- ISSN：1520-4804
文摘
A set of 30 novel 
8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensionalquantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA)and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination ofmolecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the mostpotent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the templateand CB1 and CB2 pharmacophore models were developed. These models were fitted with experimentalbinding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFAand CoMSIA approaches show that steric effects dominantly determine the binding affinities. The CoMFAand CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptorsallowed us to deduce the possible optimal binding positions. This information can be used for the design ofnew CB analogues with enhanced activity and other tailored properties.
8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensionalquantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA)and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination ofmolecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the mostpotent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the templateand CB1 and CB2 pharmacophore models were developed. These models were fitted with experimentalbinding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFAand CoMSIA approaches show that steric effects dominantly determine the binding affinities. The CoMFAand CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptorsallowed us to deduce the possible optimal binding positions. This information can be used for the design ofnew CB analogues with enhanced activity and other tailored properties.