An updated unified pharmacophore model of the benzodiazepine binding site on gamma-aminobutyric acid(a) receptors: correlation with comparative models.
A successful unified pharmacophore/receptor model which has guided the synthesis of subtype selective compounds is reviewed in light of recent developments both in ligand synthesis and structural studies of the binding site itself. The evaluation of experimental data in combination with a comparative model of the alpha1beta2gamma2 GABA(A) receptor leads to an orientation of the pharmacophore model within the Bz BS. Results not only are important for the rational design of selective ligands, but also for the identification and evaluation of possible roles which specific residues may have within the benzodiazepine binding pocket.
Clayton
T
T
Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee, Milwaukee, WI 53201, USA.
Chen
J L
JL
Ernst
M
M
Richter
L
L
Cromer
B A
BA
Morton
C J
CJ
Ng
H
H
Kaczorowski
C C
CC
Helmstetter
F J
FJ
Furtmüller
R
R
Ecker
G
G
Parker
M W
MW
Sieghart
W
W
Cook
J M
JM
D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism; D018756:GABA Antagonists / Q000737:chemistry / Q000378:metabolism*; D018757:GABA Modulators / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008954:Models, Biological; D015394:Molecular Structure; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism*
D005419:Flavonoids; D018756:GABA Antagonists; D018757:GABA Modulators; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid