Morphine and other opioids exert their effects by activation of opioid receptors, which belong to the G protein-coupled receptor (GPCR) superfamily. Clinically used opioids exert their effects through the mu opioid receptor although two other types of opioid receptors (delta and kappa) exist. Opioid receptors couple to Galpha-i/o proteins and agonists produce inhibition of adenylyl cyclase enzymes and Ca2+ channels with activation of K+ channels. Chronic activation of mu receptors is known to produce adaptive side effects including tolerance and dependence, limiting the long-term utility of opioids as pain-relieving agents. In this thesis, I examined the ability of the delta antagonist naltrindole to prevent acute antinociceptive tolerance after a single dose of the mu agonist morphine. I demonstrate reduced mu agonist-induced antinociceptive tolerance with delta antagonist administration in vivo. Ex vivo, morphine exposure produced a decrease in high-affinity mu receptors and decreased ability of subsequent mu agonist to stimulate G protein. These effects were reversed with delta antagonist administration. Evidence for interactions between mu and delta receptors in the production of tolerance has furthered interest in novel drugs devoid of tolerance liability. Based on experiments in this thesis and previous reports, compounds displaying mu agonism for appropriate analgesia with delta antagonism to prevent tolerance development are desirable. Therefore, I synthesized bifunctional opioid peptide ligands displaying this mixed efficacy profile with equivalent binding affinities to both mu and delta receptors. Novel opioid peptides were synthesized using both tetra- and pentapeptide scaffolds. Naphthylalanine-substituted pentapeptide ligands identified a novel mu/kappa agonist, delta partial agonist/antagonist peptide. Development of tetrapeptide ligands led to the characterization of KSK-103, which demonstrated mu agonist efficacy on par with the clinical standard morphine and delta antagonism at both the level of G protein stimulation and inhibition of adenylyl cyclase. In silico docking of peptides in computational models of the putative ‘active’ and ‘inactive’ conformations of the mu and delta receptors revealed steric hindrance in binding the delta ‘active’ conformation, potentially preventing delta agonist efficacy. These studies highlight the potential of bifunctional ligands displaying mu agonism and delta antagonism in producing analgesia without the limitations of tolerance development
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