Date of Award

5-2011

Level of Access

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Edward Bilsky

Second Committee Member

Alan Rosenwasser

Third Committee Member

Harold Dowse

Abstract

Acute and chronic pain present major medical problems worldwide, having negative impacts on human health. Current analgesic therapies provide incomplete pain relief and side effects in many patients, limiting their clinical utility. Peptide-based drug candidates offer several advantages over small molecule pharmaceuticals. The primary obstacles hindering development of peptide-based drugs have been related to pharmacokinetic issues including oral bioavailability, serum stability and poor penetration of the blood-brain barrier (BBB). A primary goal of this dissertation was to further advance strategies to improve delivery of peptide-based drugs into the CNS. Previous work demonstrated that glycosylation of small enkephalin-based peptides increases stability and BBB penetration. Glycosylation and phosphorylation of opioid peptides were further investigated. Both strategies increased the water solubility of the parent peptide but did not decrease receptor affinity for mu or delta opioid receptors. The compounds retained excellent antinociceptive potency when injected directly into the CNS and modification increased systemic potency (glycosylation > phosphorylation). Ongoing studies are now assessing the effects of glycosylation on larger deltorphin- and endorphin-based peptides to assess the generality of the glycosylation strategy for improving CNS bioavailability. Another primary goal was to assess the feasibility of developing mixed acting delta/mu agonists as a novel analgesic drug class. It was hypothesized that mixed delta/mu opioid glycopeptides would exhibit more favorable preclinical profiles in models of acute and chronic pain with fewer associated side effects compared to mu selective agonists. To test this hypothesis, we characterized the in vitro and in vivo activity of MMP-2200, a glycopeptide having high affinity and efficacy at delta and mu opioid receptors. MMP-2200 produced broad-spectrum antinociceptive activity following systemic administration in preclinical models of acute and chronic pain. MMP-2200 also exhibited reduced addiction liability, reduced muscular rigidity, and reduced tolerance and physical dependence when compared to equivalent doses of morphine. The compound was equivalent to morphine with respect to inhibition of gastrointestinal motility and respiratory depression. These studies have helped to further define the optimal ratio of delta selectivity in terms of maximizing analgesic efficacy with fewer classic opioid mediated side effects.

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