Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy.
Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors facilitate synaptic plasticity and can improve various forms of learning and memory. These modulators show promise as therapeutic agents for the treatment of neurological disorders such as schizophrenia, ADHD, and mental depression. Three classes of positive modulator, the benzamides, the thiadiazides, and the biarylsulfonamides differentially occupy a solvent accessible binding pocket at the interface between the two subunits that form the AMPA receptor ligand-binding pocket. Here, we describe the electrophysiological properties of a new chemotype derived from a structure-based drug design strategy (SBDD), which makes similar receptor interactions compared to previously reported classes of modulator. This pyrazole amide derivative, JAMI1001A, with a promising developability profile, efficaciously modulates AMPA receptor deactivation and desensitization of both flip and flop receptor isoforms. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1617, USA. jonathan.harms@colostate.edu
Jonathan E
JE
Harms
Morris
M
Benveniste
John K F
JK
Maclean
Kathryn M
KM
Partin
Craig
C
Jamieson
D000081:Acetamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000495:Allosteric Site; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D030562:Databases, Protein; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D021122:Protein Subunits / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
C578110:2-(2-(4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7 tetrahydrobenzo(b)thiophene-3-carboxamide; D000081:Acetamides; D001549:Benzamides; D018690:Excitatory Amino Acid Agonists; D008024:Ligands; D018697:Nootropic Agents; D021122:Protein Subunits; D011720:Pyrazoles; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D013876:Thiophenes