Functional insight into development of positive allosteric modulators of AMPA receptors

Abstract

Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) ionotropic glutamate receptors facilitate synaptic plasticity and contribute essentially to learning and memory, properties which make AMPA receptors targets for drug discovery and development. One region at which several different classes of positive allosteric modulators bind lies at the dimer interface between the ligand-binding core of the second, membrane-proximal, extracellular domain of AMPA receptors. This solvent-accessible binding pocket has been the target of drug discovery efforts, leading to the recent delineation of five “subsites” which differentially allow access to modulator moieties, and for which distinct modulator affinities and apparent efficacies are attributed. Here we use the voltage-clamp technique in conjunction with rapid drug application to study the effects of mutants lining subsites “A” and “B” of the allosteric modulator pocket to assess affinity and efficacy of allosteric modulation by cyclothiazide, CX614, CMPDA and CMPDB. A novel analysis of the decay of current produced by the onset of desensitization has allowed us to estimate both affinity and efficacy from single concentrations of modulator. Such an approach may be useful for effective high throughput screening of new target compounds.

AMPA receptor potentiators: from drug design to cognitive enhancement

“…Modulators have been shown to bind in three “modes” related to occupancy of this pocket [35]: 1) two molecules of modulator binding perpendicular to the 2-fold axis of symmetry of the LBD dimer, such as cyclothiazide; 2) two overlapping conformations of modulator within the central site (subsite A), such as CX614; and 3) chemically symmetrical compounds that bind to subsite A with a single conformation, such as CMPDA. Structure-function work on positive allosteric modulators that interact with this site consistently reveal that modifications of either moieties on the compound or the amino acid sidechains on the receptor, which alter the number of contacts or the strength of the interactions between the compounds, water molecules and protein sidechains within the five subsites, determine both efficacy and affinity [10,41]. However, our understanding of the interactions had not seemed robust enough to allow completely accurate predictive modeling of the activity of newly synthesized compounds.…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…Intense modification to AMPA receptor activity is described as a condition in many disorders, for example, by evaluating that AMPA receptor hyper‐activation is potently excitotoxic . Therefore the AMPA receptor and its most representative subunits (GluA) are significant therapeutic targets for a wide range of diseases such as AD, Parkinson's disease, autism, schizophrenia, and stroke …”

“…This approach is expected to improve the selectivity of these modulators, thus increasing the chances of keeping GluA in the open state, consequently improving the synaptic events related to AMPA receptors. Finally, this should contribute to learning and memory properties, ameliorating the conditions observed in such CNS disorders as AD …”

“…[216] Therefore the AMPA receptor andits most representative subunits (GluA) are significant therapeutic targets for aw ide range of diseases such as AD, Parkinson's disease, autism, schizophrenia, and stroke. [222][223][224][225] Because variousr eceptors are composed of the GluA subunit, and as direct agonists of these receptors are frequently associated with excitotoxic side effects, researchers have directed their efforts toward the use of PAMs of AMPAr eceptors as a strategy. [217] This approachi se xpectedt oi mprove the selectivity of these modulators, thus increasing the chances of keeping GluA in the open state, consequently improving the synaptic events relatedt oA MPAr eceptors.…”

AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

“…Furthermore, this understanding has been applied to the discovery of new modulators described below [11,12]. Additionally mutagenesis experiments have helped further understand the binding mode and how this influences the mechanism of action of positive allosteric modulators of the AMPA receptor [13].…”