This proposal represents an integrated program involving synthesis, conformations analyses and biological studies. We are continuing our program on the synthesis of peptidomimetic opioids incorporating B,B-dimethylated amino acid building blocks, lanthionines, aamine and lactam-bridged structures into dermorphin-deltorphin and enkephalin analogs. Our laboratories have prepared many of these target molecules. We will now undertake the synthesis of B,B-dialkylated amino acids and amine-bridged structures aimed at molecules recognized at the o-receptor. From preliminary experiments on dynorphins, we have obtained highly K selective modified structures. These findings will be applied to the synthesis of dynorphin structures with turn-inducing peptidomimetic residues at position three. Finally, we plan to synthesize a family of pyridone scaffolds containing the opioid pharmacophores. These target molecules will be obtained using novel Diels-Alder chemistry based on reactions of modified Danishevsky dienes with specifically prepared imines. Conformational studies of representative examples of each of the classes of target molecules will be undertaken using NMR and molecular modeling. Where appropriate, x-ray crystallography will be employed to obtain conformational information. During these studies, biological assays will be carried out. The synthetic strategies will be driven by direct assessment of binding profiles and biological activity. We will define u, o and k affinity in high through-put binding assays. Products with appropriate affinity will then be examined in vitro to established their agonist (or antagonist) potency in blocking evoked contraction in the guinea pig ileum (GPI: u/k), mouse vas deferens (MVD: o) and on the evoked release of the primary afferent peptide substance P from spinal cord minces (U/ok). The target drugs will then be examined for their ability to block the thermal escape test with intrathecal delivery in rats with chronic spinal catheters and with intraplantar (foot pad) injection after induction of a local thermal injury leading to a local opiate sensitive hyperalgesia. This analytical sequence will provide an efficient and essential correlation of biological effects with defined structure. The spinal substance P release studies coupled with the in vivo analgesic bioassay will provide data necessary to define the receptor properties of the test molecule. These models are reliable predictors for the activity of spinally and topically delivered opiates in humans. As such the information will provide important information for the practical development of clinically useful drugs.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-5 (01))
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Hillery, Paul
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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