This proposal has two specific aims unified by a common theme: the development of click chemistry probes to study the modulation of NMDA receptors (NMDARs), important targets for neuropsychiatric disease, by two structurally and mechanistically distinct classes of endogenous steroids. Nothing is known about how either class of steroids is trafficked or compartmentalized in neurons, even though compartmentalization can affect the ability of steroids to reach NMDA receptors and may aid identification of transport proteins involved in trafficking or other novel targets. Additionally, while some structure-activity studies have been interpreted to imply the existence of specific steroid binding sites for steroids on NMDA receptors, direct proof of direct binding is lacking. The novels probes developed in this proposal will address these two fundamental mechanistic questions. These NMDAR probes are significant because NMDA receptors, key receptors for the excitatory neurotransmitter glutamate, are of interest for medical reasons, i.e.: 1) NMDA receptor inhibition is a potential treatment for clinical depression and other neuropsychiatric disorders, and 2) modest increases in NMDA activation enhance memory and learning. Additionally, the click chemistry tools developed in the proposal will be of widespread use to scientists exploring the physiology and pharmacology of steroid modulators of NMDA receptors.
Health Relevance Modulators of NMDA receptors have been recognized as therapeutics for the treatment of neuropsychiatric disorders. We will develop click chemistry tools to elucidate the cell biological and biochemical factors that affect the modulation of these receptors by two different classes of endogenous neurosteroids. The information obtained will be useful for designing future drugs for treating neuropsychiatric disorders.