AbstractGlutamate receptor is considered to be the most fundamental neurotransmitter in the human body. It is responsible for the fast excitatory neurotransmission in the central nervous system and is involved in the synaptic plasticity modulation. Many glutamate receptors are considered as therapeutic target sites for neuropsychiatric diseases such as Alzheimer’s disease, epilepsy, schizophrenia and major depression disorder. For example, ketamine, one of the noncompetitive NMDA receptor antagonist exhibits remarkable rapid and sustaining antidepressant effects. However, these compounds also exhibited adverse dissociative effects and raised the issue of abuse liability.
Since there are colossal potentials for NMDA receptor related compounds to become therapeutic targets for severe neurological disorders with significant unmet needs, pharmacokinetic profiling of dissociative antagonists could help eliminating these adverse effects when producing effective and safe novel drug targets.
In this study, several psychotomimetic effects yielding NMDA receptor antagonists including some of the low-profile designer drugs such as diphenidine and its derivatives as well as ephenidine, which became very popular over their ketamine-like hallucinating property, have been studied via receptor binding assays, as well as pre-pulse inhibition behavior tests to measure the sensory motor gating properties. Their ability to affect NMDA receptor mediating fEPSPs and synaptic strength has also been examined via electrophysiological methods such as in vitro field recording and whole cell patch clamp recording.
It has been demonstrated that these designer drugs are selective, potent and voltage-dependent NMDA receptor antagonist via pharmacological and electrophysiological methods. Synaptic plasticity modulating effect of ketamine, D-AP5, memantine and ephenidine as well as ketamine’s metabolite (2S,6S)- and (2R,6R)-HNK have also been investigated in the present study.
|Date of Award||19 Mar 2019|
|Supervisor||Stafford L Lightman (Supervisor) & Graham Collingridge (Supervisor)|