Year of Publication

2006

Document Type

Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Peter A. Crooks

Abstract

The N-methyl-D-aspartate (NMDA) receptors are highly regulated ligand-gated ion channels, which are affected by many substrates. Overactivation of the NMDA receptor can lead to hyperexcitability and a number of neurotoxic effects and neurological diseases. Agmatine has been demonstrated to act allosterically as an inhibitory modulator at the polyamine recognition sites of the NMDA receptor complex. The present study synthesized and evaluated a library of agmatine analogs for their ability to displace tritiated MK-801 from NMDARs in P2 membrane preparations from rat brains at ligand concentrations of 1 mM and 50 uM. A full dose-response curve was generated for the most active compounds, in the presence and absence of a pathological level of spermidine (100 uM). A forty-five member subset of arylidenamino-guanidino compounds was synthesized and all were demonstrated to be NMDA receptor inhibitory modulators in the above assay. Three of these compounds generated biphasic curves, indicating activity at two binding sites: the postulated high-affinity agmatine binding site, and a low-affinity site (perhaps the channel itself). (4-Chlorobenzylidenamino)-guanidine hydrochloride demonstrated an IC50 of 3.6 uM at the former site and 124.5 uM at the latter. Several computer models were generated to direct further synthesis. Based on the structure-activity relationship of the arylidenamino-guanidino compounds, a pharmacophore model of the agmatine binding site of the NMDAR was proposed.

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