There is an urgent clinical need for the development of opioid analgesics with novel biological activity profiles that lack the limiting side effects of currently available opiates. This project concerns the development of ? opioid agonists and of compounds with mixed ?/? activity profiles as pharmacological tools and as analgesics expected to produce fewer side effects.
In Specific Aim 1, ? opioid peptide agonists containing novel phenylalanine analogues in place of tyrosine-1 will be synthesized. These compounds have been designed to have distinct ? opioid receptor binding modes and to induce or recognize a distinct receptor conformation. Therefore, these compounds may behave as functionally selective or biased ? agonists with regard to receptor signaling or internalization and have potential as analgesics with reduced side effects (e.g. tolerance development). Some of these peptides will be prepared in glycosylated form to improve blood-brain barrier (BBB) permeability. The compounds will be pharmacologically characterized in opioid receptor binding assays and functional assays, ? receptor phosphorylation and internalization studies, electrophysiological studies (Ca2+ channel activity) and bioluminescence resonance energy transfer (BRET) experiments for the identification of ? receptor interactions with various signaling effectors and ?-arrestin. Two inflammatory pain models will be used to determine antinociceptive potencies and analgesic tolerance development.
Specific Aim 2 is based on the observation that co-administered ? and ? opioid agonists act synergistically to produce a potent antinociceptive effect, thus providing the rationale for the development of mixed ? agonist/? agonists as centrally acting analgesics producing fewer side effects. It is proposed to prepare novel bifunctional compounds incorporating various ? opioid agonists linked to the opioid peptide [Dmt1]DALDA which has a dual role as ? agonist component and as BBB-penetrating vector. Compounds will be characterized in vitro and their antinociceptive potencies will be determined in acute pain models. Their propensities to produce analgesic tolerance, physical dependence, constipation and respiratory depression will be examined.
Specific Aim 3 concerns the continued development of mixed ? agonist/? antagonists with demonstrated potential as centrally acting analgesics having low propensity to produce the typical side effects of ? agonists like morphine. One design of such bifunctional compounds makes again use of [Dmt1]DALDA as ? agonist component and BBB-penetrating vector to which various ? neutral antagonists, inverse agonists or partial agonists will be linked. In another design glycosylated analogues of the ? agonist/? antagonist DIPP-NH2[?] will be prepared in an effort to improve its ability to cross the BBB. The in vitro and in vivo pharmacological characterization will be as in Aim 2.
The treatment of severe pain relies heavily upon opioid analgesics, but currently available opiates produce a number of side effects that often limit their use. One of the goals of this project is to develop opioid compounds with novel biological activity profiles as analgesics that produce little or no tolerance and physical dependence. If successful, it would represent a major advance in the field of opioid analgesics and would diminish the illicit use of opioids because of the expected low addiction liability of the proposed compounds. Another goal of the project is the development of novel opioid compounds expected to be more efficacious than morphine for the treatment of inflammatory and neuropathic pain conditions.
|Gendron, Louis; Cahill, Catherine M; von Zastrow, Mark et al. (2016) Molecular Pharmacology of Î´-Opioid Receptors. Pharmacol Rev 68:631-700|
|Tan, Paul; Blais, Carolane; Nguyen, Thi M-D et al. (2016) Prorenin/renin receptor blockade promotes a healthy fat distribution in obese mice. Obesity (Silver Spring) 24:1946-54|
|Weltrowska, Grazyna; Nguyen, Thi M-D; Chung, Nga N et al. (2016) A Cyclic Tetrapeptide (""Cyclodal"") and Its Mirror-Image Isomer Are Both High-Affinity Î¼ Opioid Receptor Antagonists. J Med Chem :|
|Cai, Yunxin; Lu, Dandan; Chen, Zhen et al. (2016) [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1. Bioorg Med Chem Lett 26:3629-31|
|Guillemyn, Karel; Starnowska, Joanna; Lagard, Camille et al. (2016) Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain. J Med Chem 59:3777-92|
|Betti, Cecilia; Starnowska, Joanna; Mika, Joanna et al. (2015) Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics. ACS Med Chem Lett 6:1209-14|
|MÃ¶rÃ¶y, Tarik; Vassen, Lothar; Wilkes, Brian et al. (2015) From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation. Blood 126:2561-9|
|Schiller, Peter W; Nguyen, Thi M-D; Saray, Amy et al. (2015) The bifunctional Î¼ opioid agonist/antioxidant [Dmt(1)]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type i. ACS Chem Neurosci 6:1789-93|
|Fenalti, Gustavo; Zatsepin, Nadia A; Betti, Cecilia et al. (2015) Structural basis for bifunctional peptide recognition at human Î´-opioid receptor. Nat Struct Mol Biol 22:265-8|
|Guillemyn, Karel; Kleczkowska, Patrycia; Lesniak, Anna et al. (2015) Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics. Eur J Med Chem 92:64-77|
Showing the most recent 10 out of 98 publications