Synthesis, molecular modeling and QSAR studies in chiral 2,3-disubstituted-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indoles as potential modulators of opioid antinociception

In view of coexistence of opioid and cholecystokinin (CCK) in the brain are as concerned with pain processing, some semirigid racemic and chiral analog ues of a potent CCK receptor antagonist (benzotript) have been synthesized and tested for their modulatory role on opioid antinociception, which may b e mediated by CCK-B receptor. Some of these compounds, 3e, 3g, 3h, 4a, 4b a nd 4h, exhibited antinociceptive potentiation comparable to benzotript and proglumide. In order to identify the essential chemical structural features important for this potentiation, molecular modeling and quantitative struc ture activity relationship (QSAR) studies have been carried out in the S an d R enantiomers of some of these semi-rigid compounds. The 3D-biophore mode ls, common to all molecules of the training set have been derived. These mo dels with superimposition (match value > 0.25) depicted three biophoric sit es one each for, pi /hydrophobic interactions, hydrogen bonding and ionic i nteractions among the phenyl/pyrrole ring, indole nitrogen, amidic oxygen, pyridyl nitrogen and lone pair of amidic oxygen. The total hydrophobicity a nd S absolute stereochemistry are found to positively contribute to potenti ation of antinociception induced by morphine and the resulting quantitative pharmacophoric model with good correlation is found to well describe the o bserved activity. (C) 2001 Elsevier Science Ltd. All rights reserved.