Date of Award

5-12-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Rachel Steinhardt

Subject Categories

Chemistry | Physical Sciences and Mathematics

Abstract

The field of neuroscience is rapidly evolving and so the development of novel tools that support innovative research is urgently needed. Two tools that have proven to be particularly impactful to the field of neuroscience are activity-based protein profiling (ABPP) and optogenetics, both of which have seen widespread application but with relatively limited advancement of the underlying technology. Limitations of ABPP and optogenetics have become increasingly apparent and research output is stalling due to lack of technological advancement. For example, few systems exist for targeting low-abundance and unstable proteins via ABPP and application of ABPP and optogenetic systems thus far has largely demonstrated the technology’s utility across families of receptors rather than subtype specific targets.1-11 Direct modulation of subtype specific endogenous neuroreceptor activity is key to connecting molecular and systems neuroscience, so next generation molecular tools to address these limitations possess huge potential. Here, we have demonstrated (1) The development and application of photoactivatable forms of WAY-161503 and N-desmethylclozapine (NDMC), designed as a system that enables spectrally multiplexed, spatiotemporal controlled modulation of native human serotonin receptor 2C (5-HT2C) calcium (Ca2+) signaling and (2) The design and use of bioactive photoaffinity probes for human dopamine receptor D2 (DRD2), which demonstrate excellent activity in “workhorse” biochemical assays, receptor labeling, cell labeling, and chemoproteomics. The advancements of these technologies demonstrate an important step forward for optogenetics, where modulation of endogenous neuroreceptors has proven to be a challenge, and for ABPP, where underrepresentation of low-abundance and unstable proteins has limited the scope of advancements in the field of proteomics. Future work will continue to develop neuroreceptor targeted photoactive probes, with lysergic acid (LSA) derivatives providing an initial family of targets that are both synthetically interesting and biologically important to the fields of neuroscience, chemical biology, and medicinal chemistry.

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Open Access

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