Doctor of Philosophy (PhD)
Pharmacology and Experimental Neuroscience
Daniel T. Monaghan, Ph.D.
The N-methyl-D aspartate receptors (NMDARs) are ligand-gated ion channels, which play important roles in learning and memory. Excessive activity of NMDARs is implicated in damage due to stroke and neurodegenerative diseases, whereas hypoactivity of NMDARs contributes to schizophrenia. The initial goal of my dissertation is to evaluate the potential role of the GluN2D-containing NMDARs in neuropathological, behavioral and cognitive alterations associated with schizophrenia and characterize the pharmacology and mechanisms of action of NMDAR modulators which could potentially be used to modulate these receptors in schizophrenia.
A subanesthetic dose of the NMDAR antagonist ketamine elicits symptoms of schizophrenia. This property led to the well-supported theory of NMDARs-hypofunction in schizophrenia. We found that ketamine increases [14C]-2-deoxy-glucose uptake in the medial prefrontal cortex and entorhinal cortex in wild type (WT) but not in GluN2D-knock out (KO) mice. Ketamine also increases locomotor activity and gamma-band oscillatory power in WT but not in GluN2D-KO mice. These results suggest a critical role of GluN2D-containing NMDARs in ketamine-induced schizophrenia-like symptoms in mice. Also, consistent with a role for GluN2D in schizophrenia is that the GluN2D-KO mice displayed impaired spatial memory acquisition and reduced parvalbumin (PV)-immunopositive staining compared to control mice.
To develop NMDAR modulator for treating schizophrenia and other neurological diseases, we characterized several different naphthalene and phenanthrene based compounds for their positive allosteric modulator (PAM), negative allosteric modulator (NAM) and competitive antagonistic activity at NMDARs. We discovered that UBP684 and UBP753 are general NMDAR PAMs, UBP792 is a GluN2C/GluN2D-preferring NAM and UBP791 is a GluN2C/GluN2D-preferring competitive antagonist.
Subsequent studies identified the mechanisms of action of the new compounds. The general PAMs UBP684/UBP753 increase agonist efficacy. They increase the channel open probability (Popen), and prolong the deactivation time upon glutamate removal. They bind to both the inactive and active states of the receptor and stabilize the glutamate-bound state of the GluN2 ligand-binding domain (LBD). The GluN2C/GluN2D-selective NAM UBP792 is a non-competitive antagonist and acts in a voltage-independent manner. Like the PAMs UBP684 and UBP753, UBP792 also acts by stabilizing the GluN2 LBD.
Sapkota, Kiran, "Target Validation and Pharmacological Characterization of Novel NMDAR Modulators" (2016). Theses & Dissertations. 177.