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 areas concerned with pain processing, some semirigid racemic and chiral analogues of a potent CCK receptor antagonist (benzotript) have been synthesized and tested for their modulatory role on opioid antinociception, which may be mediated by CCK-B receptor. Some of these compounds, 3e, 3g, 3h, 4a, 4b and 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 structure activity relationship (QSAR) studies have been carried out in the S and R enantiomers of some of these semi-rigid compounds. The 3D-biophore models, common to all molecules of the training set have been derived. These models with superimposition (match value >0.25) depicted three biophoric sites one each for, pi/hydrophobic interactions, hydrogen bonding and ionic interactions among the phenyl/pyrrole ring, indole nitrogen, amidic oxygen, pyridyl nitrogen and lone pair of amidic oxygen. The total hydrophobicity and S absolute stereochemistry are found to positively contribute to potentiation of antinociception induced by morphine and the resulting quantitative pharmacophoric model with good correlation is found to well describe the observed activity.
Saxena
A K
AK
Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India. anilsak@hotmail.com
Pandey
S K
SK
Tripathi
R C
RC
Raghubir
R
R
D018712:Analgesics, Non-Narcotic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011377:Proglumide / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D001549:Benzamides; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D011377:Proglumide; C013841:benzotript