A structure-activity relationship study of the affinity of selected imidazo[1,2-a]pyridine derivatives, congeners of zolpidem, for the omega 1-subtype of the benzodiazepine receptor.
A series of 6-substituted 2-aryl-N,N-dimethylimidazol[1,2-a] pyridine-3-acetamides, congeners of zolpidem and alpidem, was synthesized and tested in vitro for binding with the benzodiazepine receptor in the competition with 3H-zolpidem as an omega 1-selective radioligand. Molecular electrostatic potential (MEP) and the HOMO and LUMO energies were calculated for the compounds by semi-empirical quantum chemistry methods. The lipophilicity parameter of the compounds, expressed as the logarithm of the octanol-water partition coefficient (log P), was calculated; alternatively, standard values of the Hansch hydrophobic substituent constants pi were used. In agreement with earlier investigations on the benzodiazepine receptor ligands with a high preference for the omega 1-subtype, a quantitative correlation of the biological data with molecular parameters has revealed a significant dependence (r = 0.954) of the binding affinity (IC50) on the deepest MEP minimum, in this case associated with the amide carbonyl oxygen atom. The lipophilicity parameters were found to be of lower significance.
Lange
J
J
Chemistry Department, University of Technology, 3 Noakowskiego Str., 00-664 Warsaw, Poland.
Karolak-Wojciechowska
J
J
Wejroch
K
K
Rump
S
S
D000818:Animals; D003975:Diazepam / Q000737:chemistry; D018755:GABA Agonists / Q000737:chemistry / Q000378:metabolism*; D018757:GABA Modulators / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D000077334:Zolpidem
D018755:GABA Agonists; D018757:GABA Modulators; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; C001439:imidazo(1,2-a)pyridine; D003975:Diazepam