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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004443-25
Application #
8646890
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (91))
Program Officer
Rapaka, Rao
Project Start
1987-06-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
25
Fiscal Year
2014
Total Cost
$223,630
Indirect Cost
$16,565
Name
Clinical Research Institute of Montreal
Department
Type
DUNS #
201373169
City
Montreal
State
QC
Country
Canada
Zip Code
H2 1-R7
Ballet, Steven; Betti, Cecilia; Novoa, Alexandre et al. (2014) In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues. ACS Med Chem Lett 5:352-357
Charfi, Iness; Nagi, Karim; Mnie-Filali, Ouissame et al. (2014) Ligand- and cell-dependent determinants of internalization and cAMP modulation by delta opioid receptor (DOR) agonists. Cell Mol Life Sci 71:1529-46
Bai, Longxiang; Li, Ziyuan; Chen, Jiajia et al. (2014) [Dmt(1)]DALDA analogues with enhanced ? opioid agonist potency and with a mixed ?/? opioid activity profile. Bioorg Med Chem 22:2333-8
Tudashki, Hanieh Bagheri; Robertson, Derek N; Schiller, Peter W et al. (2014) Endocytic profiles of ýý-opioid receptor ligands determine the duration of rapid but not sustained cAMP responses. Mol Pharmacol 85:148-61
Chen, Bainian; Zhao, Qing; Ni, Rui et al. (2014) Inhibition of calpain reduces oxidative stress and attenuates endothelial dysfunction in diabetes. Cardiovasc Diabetol 13:88
Weltrowska, Grazyna; Lemieux, Carole; Chung, Nga N et al. (2014) 'Carba'-carfentanil (trans isomer): a ? opioid receptor (MOR) partial agonist with a distinct binding mode. Bioorg Med Chem 22:4581-6
Jida, Mouhamad; Betti, Cecilia; Schiller, Peter W et al. (2014) One-pot isomerization-cross metathesis-reduction (ICMR) synthesis of lipophilic tetrapeptides. ACS Comb Sci 16:342-51
Weltrowska, Grazyna; Nguyen, Thi M-D; Chung, Nga N et al. (2013) N-terminal guanidinylation of TIPP (Tyr-Tic-Phe-Phe) peptides results in major changes of the opioid activity profile. Bioorg Med Chem Lett 23:5082-5
Ding, Jinguo; Lemieux, Carole; Chung, Nga N et al. (2012) Bifunctional ýý/ýý opioid peptides: variation of the type and length of the linker connecting the two components. Chem Biol Drug Des 79:186-93
Ciszewska, Malgorzata; Ruszczynska, Katarzyna; Oleszczuk, Marta et al. (2011) Cyclic enkephalin-deltorphin hybrids containing a carbonyl bridge: structure and opioid activity. Acta Biochim Pol 58:225-30

Showing the most recent 10 out of 81 publications