Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

David R. Worthen

Abstract

Epilepsy is a disorder characterized by the occurrence of seizures, which are periods of abnormally excessive synchronous neuronal activity in the brain. Affecting over 70 million people worldwide, many of whom do not respond to pharmacotherapy, there is a need for novel anticonvulsant compound discovery. Diaminodiphenyl compounds, a class of compounds shown to present anticonvulsive effects in vivo have been purported to exert their effects on the N-methyl-D-aspartate receptor (NMDAr); an excitatory, ionotropic receptor that is a key player in the functions of the glutamatergic system. The glutamatergic system is vital in the promotion of synaptic plasticity and has been implicated in a myriad of mental health issues, including epilepsy. We hypothesize that diaminodiphenyl compounds interact with NMDAr at an allosteric binding site on the NR2 subunit which is activated by the agonist glutamate. This project is intended to characterize the diaminodiphenyl binding interactions with NMDAr, elucidate a structure activity relationship between diaminodiphenyl compounds and NMDAr and create novel diaminodiphenyl compounds employing rational drug design to improve the therapeutic index of the compounds. The data presented in the following manuscripts characterizes a novel binding motif between diaminodiphenyl compounds and NMDAr using computer based modeling techniques. A structure activity relationship was derived by examining the anticonvulsant effects of several different diaminodiphenyl compounds in animal models of epilepsy. Employing the computationally derived binding motif and structure activity relationship, several diaminodiphenyl derivatives have been designed in an effort to alleviate metabolic toxicity and improve anticonvulsive potency. Rational drug design targeting the described diaminodiphenyl binding site could offer novel anticonvulsants which act through a novel mechanism on NMDAr. Antagonism of NMDAr is not limited to epilepsy alone, NMDAr has been implicated in a number of disease states and diaminodiphenyls could serve multiple indications such as: neuropathy, mood disorders and post stroke outcomes.

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