Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit.

Full Abstract

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.

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Author information

Author/s: Harris, Danni (D); Clayton, Terry (T); Cook, James (J); Sahbaie, Peyman (P); Halliwell, Robert F (RF); Furtmüller, Roman (R); Huck, Sigismund (S); Sieghart, Werner (W); DeLorey, Timothy M (TM);

Affiliation: Moltech Corporation, 1000 Elwell Court, Palo Alto, California 94303, USA.

Grants: MH46851 (Agency:United States NIMH) ; R43 MH070228 (Agency:United States NIMH)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of medicinal chemistry (J Med Chem), published in United States. (Language: eng)

Reference: 2008-Jul; vol 51 (issue 13) : pp 3788-803

Dates: Created 2008/07/07; Completed 2008/08/12;

PMID: 18537233, status: MEDLINE (last retrieval date: 11/6/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Behavior, Animal - drug effects
Benzodiazepines - chemistry; pharmacology
Chemistry, Physical
Computer Simulation
Databases, Factual
Electrophysiology
Female
Ligands
Male
Memory - drug effects

Memory - drug effects
Mice
Models, Molecular
Molecular Structure
Oocytes
Protein Isoforms - chemistry; metabolism
Protein Subunits - chemistry; metabolism
Quantitative Structure-Activity Relationship
Receptors, GABA-A - chemistry; metabolism
Structure-Activity Relationship
Xenopus laevis

Associated Chemicals: Benzodiazepines (0) ; Ligands (0) ; Protein Isoforms (0) ; Protein Subunits (0) ; Receptors, GABA-A (0)

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