Author ORCID Identifier

https://orcid.org/0009-0003-0684-1695

Date Available

1-23-2026

Year of Publication

2024

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

First Advisor

Dr. Thomas Prisinzano

Abstract

Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system characterized by demyelination and neuroinflammation. There is currently no cure for MS. There is a critically unmet need for the development of pharmacotherapies that can induce remyelination promoting both repair and recovery. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating pharmacotherapies. KOR activation has been shown to promote functional recovery and remyelination preclinically. However, typical KOR agonists like U50,488 have limitations such as sedation and dysphoria limiting their use. This necessitates further development of new KOR agonists that maintain efficacy while eliminating negative side effects. We aim to synthesize novel compounds promoting remyelination and recovery in demyelinating diseases such as MS.

A library of KOR agonists was synthesized and evaluated for activity. These analogs were modified using classical medicinal chemistry techniques including bioisosteric replacement, homologation, alteration of stereochemistry, alteration of interatomic distances and molecular dissection. In vitro evaluation of these analogs suggests functional selectivity for KOR. In vivo results suggest that our KOR agonists promote recovery and remyelination in CNS demyelinating disease models in a KOR-dependent fashion. Together, these results demonstrate KOR as a promising target for further development of remyelinating therapies.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.20

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Available for download on Friday, January 23, 2026

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