Dissertations & Theses - Gradworks

Abstract:

Glutamate, the principal excitatory neurotransmitter in the CNS, is implicated in numerous diseases including depression, neurodegeneration, and epilepsy. One target for preventing excessive glutamate signaling is through N-methyl-D-aspartate receptor (NMDAR) antagonism. NMDAR over-stimulation can lead to cell damage and death. A number of NMDAR antagonists have been investigated as neuroprotective agents in clinical trails of stroke and neurodegenerative disease. The psychoactive side effects have been a major limitation in the development of NMDAR antagonists. The prototypical neuroprotective NMDAR antagonist is memantine which is approved in the United Statues for moderate-severe Alzheimer’s disease. The fact that memantine is well tolerated is proof NMDAR antagonists can be tolerated.

A series of uncompetitive NMDAR antagonists of the arylcycloalkylamine class were synthesized. Compounds were investigated for NMDAR affinity, off-target receptor interactions, in vitro neuroprotective and in vivo antiepileptic action and toxicity. Compounds showed a range of affinities (K_i) for [³H]-(+)-MK-801 labeled NMDAR in rat forebrain. Affinities at 44 off-target CNS receptor sites, including serotonergic, dopaminergic, adrenergic, opioid, monoamine reuptake and sigma receptors, as well as functional potencies for monoamine reuptake were determined in collaboration with the NIMH PDSP. In vitro and in vivo neuroprotection and anticonvulsant studies were determined through the NINDS ASP. Many compounds showed good anticonvulsant effects in vivo with several showing improved protective indexes (PI) over existing NMDAR antagonist therapeutics such as memantine and ketamine. Both in vivo protection in mouse maximal electroshock seizure test (MES) model and rotarod toxicity showed good correlation with NMDAR affinity implicating NMDAR antagonism in both therapeutic activities and side effects. A non-linear relationship was identified between NMDAR affinities and PI, in which an optimal NMDAR affinity (pK_i: 6.7-7.6) and MES ED₅₀ potency range (10-35 mg/kg) were identified. Lastly, affinity at NET and SERT positively correlated with PI, suggesting a role for polypharmacological interactions in the observed therapeutic activity of arylcycloalkylamines. Finally these results support incorporation of moderate affinity NMDAR antagonism into a broader polypharmacological approach to drug therapy as opposed to the more classic “selective” approach.