Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit.
Ligands that bind to the benzodiazepine binding site on the GABA A receptor can attenuate or potentiate cognition. To investigate this property, the chemical determinants favoring selective binding or selective activation of the alpha5beta2gamma2 and alpha1beta2gamma2 GABA A receptor isoforms were examined. A 3D-pharmacophore, developed from a diverse set of BDZR ligands, was used as an initial basis for multivariate discriminant, fragment, and 3D-quantitative structure-activity relationship analyses, which formed the criteria for selection of additional compounds for study. We found that the electrostatic potential near the ligands' terminal substituent correlated with its binding selectivity toward the alpha5beta2gamma2 versus alpha1beta2gamma2 isoform; while the fragment length and frontier molecular orbital energetics correlated with a compounds influence on electrophysiological activity. Compounds with promising alpha5 profiles were further assessed for their ability to attenuate scopolamine-induced contextual memory impairment in mice. Surprisingly, both weak inverse agonist and antagonists that display binding selectivity toward the alpha5beta2gamma2 isoform were able to attenuate contextual memory impairment.
Moltech Corporation, 1000 Elwell Court, Palo Alto, California 94303, USA.
Danni
D
Harris
Terry
T
Clayton
James
J
Cook
Peyman
P
Sahbaie
Robert F
RF
Halliwell
Roman
R
Furtmüller
Sigismund
S
Huck
Werner
W
Sieghart
Timothy M
TM
DeLorey
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D016208:Databases, Factual; D004594:Electrophysiology; D005260:Female; D008024:Ligands; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009865:Oocytes; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D008024:Ligands; D020033:Protein Isoforms; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines