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Studies of a novel analgesic identified by establishing a structure-activity relationship for the analgesic prototype, isovaline

University of British Columbia

Pain is a major health concern worldwide with current drugs limited by adverse effects. Isovaline is a small amino acid analgesic which produces antinociception in animal models of pain without associated toxicity supporting it as a candidate for further development. This thesis explores isovaline’s structure-activity relationship for antinociception and investigates the antinociceptive properties of an analog, 1-amino-1-cyclobutane carboxylic acid (ACBC). Chapter 1 describes various aspects of pain including the epidemiology, neurobiology, and the efficacy and limitations of current pharmacotherapy. It also discusses methods of preclinical pain research and the potential of isovaline and ACBC as analgesics. Chapter 2 investigates the structure-activity relationship for the antinociceptive effects of isovaline and establishes a library of analogs to identify the pharmacophore for isovaline. We have demonstrated that formation of a cyclobutane ring is necessary for antinociception. The studies described herein identified ACBC as possessing antinociceptive effects without producing motor deficits. Chapter 3 further examines the antinociceptive properties of ACBC and its potential as a spinal analgesic. We found that ACBC produces robust and reversible antinociception following administration into the lumbar intrathecal space of mice. We demonstrate that the effects were localized to dermatomes related to the site of injection and did not ascend cephalad to produce antinociception in the forepaws or produce respiratory depression. We then investigated the antinociceptive actions of the analog, R-α-methylproline, and found that it did not produce antinociception, but produced behavioural abnormalities. Chapter 4 explored mechanisms that mediate the antinociceptive effects of ACBC in vivo. We found that ACBC does not behave like the NMDA glycine site antagonist, 7-chlorokynurenate (7-CK), and may be interacting in a competitive manner with 7-CK. In addition, we show that ACBC does not likely act at GABAB receptors as the observed antinociception was not affected by a GABAB antagonist. Chapter 5 discusses the significance and limitations of this work, and proposes future research that would further support ACBC as an analgesic candidate.

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2019-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/65859

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/