Pharmacophore/receptor models for GABA(A)/BzR alpha2beta3gamma2, alpha3beta3gamma2 and alpha4beta3gamma2 recombinant subtypes. Included volume analysis and comparison to alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2 subtypes.
Pharmacophore/receptor models for 6 recombinant GABA(A)/BzR subtypes (alphax beta3gamma2, x = 1-6) have been established via an SAR ligand mapping approach. This study was based on the affinities of 166 BzR ligands at 6 distinct (alpha1-6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least twelve different structural families. Examination of the included volumes indicated that the shapes of binding pockets for alpha1, alpha2 and alpha3 subtypes are very similar to each other. Region L2 for the alpha5 containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other subtypes. Moreover, region L3 in the alpha6 subtype is either very small or nonexistent in this diazepam insensitive "DI" subtype as compared to the other subtypes. Preliminary results for the alpha4-containing receptor subtype (DI) indicate that L3 in the alpha4 subtype suffers a similar fate. Use of the pharmacophore/receptor models for these subtypes have resulted in the design of novel BzR ligands selective for the alpha5beta3gamma2, receptor subtype.
He
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X
Department of Chemistry, University of Wisconsin-Milwaukee, 53201, USA.
Huang
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Q
Ma
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Yu
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McKernan
R
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Cook
J M
JM
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D005442:Flumazenil / Q000737:chemistry / Q000494:pharmacology; D018757:GABA Modulators / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011963:Receptors, GABA-A / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D018757:GABA Modulators; D008024:Ligands; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005442:Flumazenil