title: Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation.
abstract: At the dimer interface of the extracellular ligand-binding domain of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors a hydrophilic pocket is formed that is known to interact with two classes of positive allosteric modulators, represented by cyclothiazide and the ampakine 2H,3H,6aH-pyrrolidino(2,1-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1,4-dioxan-10-one (CX614). Here, we present structural and functional data on two new positive allosteric modulators of AMPA receptors, phenyl-1,4-bis-alkylsulfonamide (CMPDA) and phenyl-1,4-bis-carboxythiophene (CMPDB). Crystallographic data show that these compounds bind within the modulator-binding pocket and that substituents of each compound overlap with distinct moieties of cyclothiazide and CX614. The goals of the present study were to determine 1) the degree of modulation by CMPDA and CMPDB of AMPA receptor deactivation and desensitization; 2) whether these compounds are splice isoform-selective; and 3) whether predictions of mechanism of action could be inferred by comparing molecular interactions between the ligand-binding domain and each compound with those of cyclothiazide and CX614. CMPDB was found to be more isoform-selective than would be predicted from initial binding assays. It is noteworthy that these new compounds are both more potent and more effective and may be more clinically relevant than the AMPA receptor modulators described previously.
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1617, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Timm
authors.forename: Morris
authors.initials: M
authors.lastname: Benveniste
authors.forename: Autumn M
authors.initials: AM
authors.lastname: Weeks
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Partin
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray / Q000379:methods; D018683:Excitatory Amino Acid Agents / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D010078:Oxazines / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D018683:Excitatory Amino Acid Agents; D010078:Oxazines; D018091:Receptors, AMPA; C414782:2H,3H,6aH-pyrrolidino(2'',1''-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1, 4-dioxan-10-one; C104722:glutamate receptor ionotropic, AMPA 2