Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy

Jonathan E. Harms, Morris Benveniste, John K.F. Maclean, Kathryn M. Partin, Craig Jamieson

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Pos. 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 neurol. disorders such as schizophrenia, ADHD, and mental depression. Three classes of pos. 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 electrophysiol. 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 deriv., 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'. [on SciFinder(R)]
Original languageEnglish
Pages (from-to)45-52
Number of pages8
JournalNeuropharmacology
Volume64
DOIs
Publication statusPublished - Jan 2013

Keywords

  • electrophysiology
  • benzamides
  • cyclothiazide
  • deactivation
  • desensitization
  • kinetics

Projects

JARL Start Up Funding

Jamieson, C.

1/04/11 → …

Project: Internally funded project

Research Output

  • 23 Citations
  • 1 Chapter

AMPA receptor positive modulators

Jamieson, C., Morrow, J. & Maclean, J., Jul 2012, Targets and Emerging Therapies for Schizophrenia. Albert, J. & Wood, M. (eds.). 1 ed. Hoboken, NJ, p. 187-231 44 p.

Research output: Chapter in Book/Report/Conference proceedingChapter

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