We propose to develop novel opioid peptide analogs and derivatives with minimal side effects for use in obstetric analgesia. The structural characteristics of the new compounds should be such that they (i) retain high selectivity for either mu or delta opioid receptors, (ii) are able to penetrate the blood-brain barrier (BBB) (systemic administration) or the dura mater (epidural administration), and (iii) cannot cross the placental barrier (PB). It is expected that analgesics with this kind of profile may be discovered through structural modifications that produce considerable variation in the physico-chemical properties of already existing, receptor-selective opioid peptides. As parent peptides we will use four mu-selective opioid tetra-and dipeptide agonists and two novel dipeptide delta agonists, all of which were recently developed in the P.I.'s laboratory. We intend to achieve better penetration of the BBB by rendering the peptides more lipophilic (passage via passive diffusion) or by increasing the number of positive charges they carry (passage via non- specific, absorptive endocytosis). It is expected that a certain degree of lipophilicity and/or a certain number and distribution of positive charges may enable a peptide analog to cross the BBB but not the PB. Lipophilicity will be enhanced through incorporation of highly hydrophobic, artificial amino acids into the peptide and/or attachment of lipophilic moieties to end groups, whereas positive charges will be introduced through N- or C- terminal extension with basic amino acids and/or through peptide bond reductions or reversals. The opioid receptor affinities and selectivities of the new analogs will be determined in binding assays based on displacement of mu-, delta- and k-selective radio-ligands from rat brain or guinea pig membrane binding sites. Opioid agonist contractions of the guinea pig ileum and of the vase 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 both peripheral and central atinocipeption, and in the mouse hot plate test which detects only centrally mediated analgesic effects. Promising compounds will be synthesized on a larger scale for pharmacological and pharmacokinetic studies using chronically-instrumented pregnant sheep model to be carried out in Dr. Szeto's laboratory. The same compounds will also be prepared in deuterated form as standards for quantitative MS analyses to be performed in Dr. Desiderio's laboratory.