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Design, Synthesis, and Evaluation of CNS-Penetrant Therapeutics, Probes, and Psychostimulants

Horton, Austin
http://orcid.org/0000-0003-4849-5455
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1605791409881891

Abstract Details

2020, Doctor of Philosophy, University of Toledo, Medicinal Chemistry.
Alzheimer's disease (AD) is a progressive, neurodegenerative disease resulting in cognitive decline, dementia, and eventually death. This work investigates furoxans (1,2,5 oxadiazole N-oxides) for their utility in the treatment of AD. Furoxans are thiol dependent nitric oxide (NO) mimetics, capable of releasing NO in a cellular environment. This work focuses on attenuated furoxans, designed to release NO in a slow, controlled manner to engage the NO/sGC pathway, resulting in in the phosphorylation of CREB, increasing the production of pro-survival gene products such as BDNF. IS-1-41 was identified as a hit compound, possessing promising biological activity such as: neuroprotection, procognitive effects, and a long systemic half-life. Efforts to explore attenuated furoxans resulted in a library of more than 60 novel attenuated furoxans. Several novel attenuated furoxans were found to be neuroprotective; however, when incubated with cysteine, none were found to breakdown to release NO despite evidence showing neuroprotection was NO/sGC dependent. We investigated the bioactivation of attenuated furoxans via selenocysteine and found that, while attenuated furoxans breakdown in the presence of selenocysteine, the resulting breakdown product has not released NO. This supports the hypothesis that attenuated furoxans interact with unknown protein target(s) to release NO, providing the observed neuroprotection, which can be further explored via photolytic target ID studies. After extensive pre-clinical development, four lead candidates, IS-1-41, AH-1-91, AH-2-36, and AH-2-87 were identified and are being investigated for their utility in the treatment of AD. Tangentially, work was undertaken to establish a platform to accomplish in vivo photoaffinity target ID studies to explore the mechanism of action of β-phenethylamines with a non-biased approach. Casper zebrafish were employed as the in vivo model, as casper zebrafish lack melanin and therefore cannot block the UV irradiation from reaching the requisite environment. The β-phenethylamine chemical class was investigated to establish the in vivo photoaffinity labeling platform as it contains psychostimulatory molecules such capable of producing behavioral changes when administered to casper zebrafish while remaining synthetically accessible. In this work, a methamphetamine-derived photo-reactive probe (MAP) was synthesized and administered to casper zebrafish, producing similar behavioral changes when compared to methamphetamine (MA). Following behavioral characterization, casper zebrafish were irradiated with UV light to induce covalent modification of the target protein(s). Brain tissue was removed and analyzed via click-chemistry to visualize the covalently modified protein(s). Several unique protein bands were observed, including a protein band around 20 kDa, where co-exposure of MA and MAP resulted in reduced labeling, indicating that MA and MAP compete for binding sites in the labeled protein.
Isaac Schiefer (Committee Chair)
William Messer (Committee Member)
Zahoor Shah (Committee Member)
Erin Prestwich (Committee Member)
Wei Li (Committee Member)
364 p.
Analytical Chemistry; Chemistry; Neurosciences; Pharmaceuticals; Pharmacy Sciences
Alzheimers disease; drug development; nitric oxide; furoxan; selenocysteine; phenethylamine; methamphetamine; cathinone; target identification; photolytic; click chemistry; casper zebrafish

Recommended Citations

Citations

  • Horton, A. (2020). Design, Synthesis, and Evaluation of CNS-Penetrant Therapeutics, Probes, and Psychostimulants [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1605791409881891

    APA Style (7th edition)

  • Horton, Austin. Design, Synthesis, and Evaluation of CNS-Penetrant Therapeutics, Probes, and Psychostimulants. 2020. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1605791409881891.

    MLA Style (8th edition)

  • Horton, Austin. "Design, Synthesis, and Evaluation of CNS-Penetrant Therapeutics, Probes, and Psychostimulants." Doctoral dissertation, University of Toledo, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1605791409881891

    Chicago Manual of Style (17th edition)

toledo1605791409881891
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This open access ETD is published by University of Toledo and OhioLINK.