ORCID ID
Graduation Date
Summer 8-14-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Pharmaceutical Sciences
First Advisor
Corey R Hopkins
Abstract
Central nervous system (CNS) disorders, including chronic pain, Parkinson’s disease-associated L-DOPA-induced dyskinesia (LID), and neuropathic pain, continue to represent significant unmet medical needs due to the limited efficacy and adverse effects of current therapies. This dissertation describes the discovery and optimization of novel CNS-active small molecules through synthetic medicinal chemistry, structure–activity relationship (SAR)-driven design, and multiparameter optimization strategies. This work led to the development of ether-linked G protein-gated inwardly rectifying potassium (GIRK1/2) channel activators as potential non-opioid analgesics. Systematic scaffold optimization transformed early chemotypes with suboptimal pharmacokinetic properties into metabolically stable, CNS-penetrant molecules with improved potency and selectivity. Strategic incorporation of heterocyclic and substituted phenoxy motifs enhanced GIRK1/2 activity while maintaining favorable selectivity profiles. Lead compounds demonstrated robust in vitro activity and advanced into in vivo pain models, supporting their therapeutic potential as non-opioid analgesics.
In parallel, this dissertation explores the design and optimization of dopamine D4 receptor (D4R) antagonists and sigma-1 receptor (S1R) modulators for the treatment of LID and neuropathic pain respectively. Through rational scaffold modification and iterative SAR exploration, multiple chemotypes were identified with nanomolar D4R potency, improved receptor selectivity, and favorable pharmacokinetic characteristics. Several compounds progressed to in vivo pharmacokinetic evaluation and demonstrated promise as CNS-active tool compounds. Collectively, this research highlights the successful application of synthetic medicinal chemistry and SAR-guided optimization to advance novel multi-target CNS therapeutics with strong translational potential for pain and movement disorders.
Rights
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Recommended Citation
Nahid, Sumaiya, "Multi-Target CNS Drug Discovery Through Synthetic and SAR-Driven Optimization" (2026). Theses & Dissertations. 1081.
https://digitalcommons.unmc.edu/etd/1081