Structure elucidation and conformational properties of synthetic cannabinoids (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo [b,d]pyranyl)-2-hexyl-1,3-dithiolane and its methylated analog

The synthetic cannabinoid (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-h ydroxy-6H-dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane (AMG-3) is a cannabim imetic molecular probe with one of the highest binding affinities reported to date. Therefore, due to its potential pharmacological importance, its st ructure was sought to be elucidated and its conformational properties were studied using a combination of 1D, 2D NMR spectroscopy and molecular modell ing. The structure of its methylated analog (-)-2-(6a,7,10,10a-tetrahydro-6 ,6,9-trimethyl-6H dibenzo [b,d]pyranyl-1-methoxy)-2-hexyl-1,3 dithiolane (A MG-18), was also studied and its conformational properties were compared wi th AMG-3. AMG-18 lacks of the phenolic hydroxyl group a strict requirement for cannabimimetic activity and is almost devoid of any biological activity . The conformational analysis studies showed that 1',1' dithiolane ring res tricted the orientation preferences of alkyl chain. This may account for th e high binding affinity of AMG-3 to cananbinoid receptors. Grid scan search studies showed different preferences of possible adopting dihedral values of phenolic hydroxyl group and its methyl ether. These observations may acc ount for their differences in biological activity. (C) 1999 Elsevier Scienc e B.V. All rights reserved.