Opiate drugs are widely used for pain relief during labor and delivery, and their use is associated with a variety of adverse effects on the mother and fetus. The overall goal of this program project grant (PPG) is to develop novel opioid peptide analogs that have fewer adverse effects on the mother and fetus than the opiate alkaloids. Opioid drugs may adversely affect the fetus directly as a result of placental drug transfer, and/or indirectly by altering maternal oxygenation and uteroplacental hemodynamics. It is proposed that maternal-fetal pharmacokinetics and receptor selectivity can be used as two approaches in the design of novel opioid drugs with fewer adverse effects. It is hypothesized that the placental transfer of opioid peptide analogs to the fetus will be much more limited compared to the opiate alkaloids. It is further hypothesized that delta-selective agonists will have fewer adverse effects on the mother and fetus compared to mu-selected agonists.
The specific aims are as follows: 1) The rational design and synthesis of novel opioid peptide analogs with high selectivity for the mu and delta receptors, and with varying degrees of lipophilicity; 2) Characterization of these peptides in terms of receptor selectivity using in vitro receptor binding assays and bioassays, and screening for antinociceptive activity in mice; 3) Determination of the maternal- fetal pharmacokinetics of these synthetic opioid peptides using the chronically-instrumented pregnant sheep model; 4) Development of appropriate analytical methods to quantitate peptide analogs in maternal and fetal plasma with optimal detection sensitivity and molecular specificity; 5) Comparison of the effects of mu and delta agonists on maternal oxygenation and uteroplacental perfusion in pregnant sheep; 6) Determination of the pharmacology of mu and delta agonists in the fetal lamb, including their effects on fetal cardiovascular, respiratory, neurobehavioral, metabolic, and neuroendocrine control. The diverse nature of the proposed studies requires a multi-disciplinary group of investigators. The PD has identified three other investigators with specific expertise in the different areas to carry out this PPG. The joint effort will provide a comprehensive evaluation of the synthetic opioid peptide analogs as obstetric analgesics which cannot be achieved by any investigator alone.
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