Date Approved

8-13-2020

Embargo Period

8-14-2020

Document Type

Thesis

Degree Name

M.S. Pharmaceutical Sciences

Department

Chemistry & Biochemistry

College

College of Science & Mathematics

Advisor

Keck, Thomas M.

Committee Member 1

Wu, Chun

Committee Member 2

Caputo, Gregory

Subject(s)

Opiods; Drug development

Disciplines

Medicinal and Pharmaceutical Chemistry

Abstract

Opioids are widely used to treat acute and chronic pain. But opioid addiction to these compounds can cause social and life-threatening health problems, including the risk of overdose. In this thesis, I evaluated IBNtxA (3-iodobenzoyl naltrexamine), a novel mu opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone, in drug discrimination studies in order to better understand its subjective effects and more thoroughly its abuse liability. IBNtxA represents an intriguing lead compound for preclinical drug development specifically targeting MOR splice variants, potentially creating effective analgesics with reduced side effects. These results indicate that IBNtxA produces potent antinociception and has low abuse liability, likely driven by substantial kappa opioid receptor agonist signaling effects. I also evaluated whether a combination of drugs can produce synergistic antinociceptive effects. Using von Frey testing and hot plate procedures, I measured the antinociceptive effects of morphine, the novel alpha2/alpha3 subunit-containing GABAA receptor positive allosteric modulator MP-III-024, and their combination. Combinations of morphine and MP-III-024 produced supra-additive effects in both assays, indicating some level of synergy from these compounds. Results from these studies may lead to the development of new analgesic treatments with improved side-effect profiles, including reduced abuse liability.

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