We propose to develop highly mu receptor-selective opioid peptide analogs that display great diversity in the relative lipophilicity/hydrophilicity of their structures. Lipophilic analogs are expected to cross the blood- brain barrier (BBB) to some extent after peripheral administration, whereas the action of polar analogs will be limited to the periphery. Thus, the proposed analogs may serve as novel analgesics producing either centrally or peripherally mediated antinociception. Peripherally induced analgesia is of considerable interest, since some side effects of opioids (respiratory depression, addition liability, etc.) are thought to be centrally mediated. A certain lipophilicity/hydrophilicity balance may permit analogs to penetrate across the BBB but not across the placental barrier, and such analogs may have potential for use in obstetric analgesia. To reach these goals, we will use an interdisciplinary approach incorporating organic chemistry, peptide synthesis and extensive pharmacologic characterization. A potent lipophilic analog (H-Tyr-D-Ala- Phe-Phe-NH2) and a polar prototype analog (Tyr-D-Arg-Phe-Lys-NH2), both showing high mu receptor selectivity, will serve as lead-compounds to develop analogs with high lipophilic or polar character, respectively. The proposed design of peptide analogs will include substitution of unusual amino acids, peptide bond modifications and conformationally restricted (cyclic) analogs. The receptor affinities and selectivities of the new analogs will be determined in binding assays based on displacement of mu, delta- and kappa-selective radioligands from rat brain or guinea pig brain membrane binding sites. Opioid agonist activities of the new compounds will be evaluated in vitro in bioassays based on inhibition of electrically evoked contractions of the guinea pig ileum and of the vasa deferentia of the mouse, rat, hamster and rabbit. The relative stability of the analogs against enzymatic degradation (rat brain peptidases) will be examined. Analgesic activities of the compounds will be determined in the mouse writhing assay, a test model permitting the detection of peripheral antinociception, and in the mouse hot plate test which detects only centrally acting opioids. The occurrence of peripherally mediated analgesic effects will be demonstrated with quaternized opiate antagonists. Placental transfer and fetal effects of the opioid peptide analogs will be determined using the chronically-instrumented pregnant sheep model.
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| Schiller, P W; Nguyen, T M; Weltrowska, G et al. (1992) Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists. Proc Natl Acad Sci U S A 89:11871-5 |
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