Common cannabimimetic pharmacophoric requirements between aminoalkyl indoles and classical cannabinoids.
Aminoalkylindoles (AAIs) are structurally dissimilar from the classical cannabinoids (CCs), however, both AAIs and CCs appear to bind at the same site on the cannabinoid receptor. To obtain better insights on the structural correlation between AAIs and CCs, we have studied the conformational properties of the potent cannabimimetic AAI WIN 55212-2 and its inactive analogs using high resolution 2D NMR spectroscopy in combination with computer-assisted molecular modeling. The pharmacophoric similarities between the AAIs and the CCs were then investigated using superimposition techniques. The absolute stereochemistries of the biologically active enantiomer (-)HHC were used as superimposition points and considered as internal controls in order to test the molecular principles guiding this experiment. Our results show that the model is congruent with a superimposition in which the naphthoyl, morpholino and 3-keto groups in the AAI, respectively correspond to the side chain, cyclohexanol OH and phenolic OH of HHC. A good fit is obtained when the two biologically active antipodes are superimposed. Conversely, the fit is poor if the inactive AAI enantiomer is superimposed on the active HHC enantiomer. It can also be seen that in such an orientation a certain deviation of the C-ring from the plane of the phenol ring of the tricyclic HHC component and of the morpholinyl portion from the plane of the indole ring of WIN 55212-2 is essential for cannabimimetic activity. The inactive enantiomer WIN 55212-3 has its respective components aligned in the opposite quadrant. By comparing the stereoelectronic features of representative AAIs and CCs, we have developed a model which may help to uncover the pharmacophoric requirements of the AAIs and serve as a basis for future SAR and drug design.
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Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs 06269, USA.
Eissenstat
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Makriyannis
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D048588:Benzoxazines; D002186:Cannabinoids / Q000737:chemistry*; D002187:Cannabinol / Q000031:analogs & derivatives* / Q000737:chemistry; D003198:Computer Simulation; D007211:Indoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D009025:Morpholines / Q000737:chemistry*; D009281:Naphthalenes / Q000737:chemistry*; D013237:Stereoisomerism
D048588:Benzoxazines; D002186:Cannabinoids; D002187:Cannabinol; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; C074005:hexahydrocannabinol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone