Opiates remain among the most useful and important class of drugs in medicine, but not without problems. The recognition of the importance of treating pain has led to an increase in their overall use and, with it, an increase in diversion an abuse. Drugs capable of producing analgesia lacking these unwanted actions would be a major advance in treating pain and minimizing drug abuse. Our laboratory has synthesized a series of analogs targeting a new opioid site that have a superior pharmacological profile. They are potent analgesics, as much as 100-fold that of morphine, and yet they display no respiratory depression, physical dependence, reinforcing behavior or cross tolerance to morphine. Our goal in this proposal is to further expand the structure-activity of these compounds by using two scaffolds that have not been examined previously on this target. We also propose to design and synthesize additional chemical probes suitable for further exploring the pharmacology of opioids and the biochemical mechanisms of their actions. This work will focus upon the generation of novel radiolabeling techniques to permit the identification of potential new targets and affinity labels.

Public Health Relevance

This proposal explores new potential targets for medication development and for agents to facilitate our understanding of opioid action. The major aims of the proposal explore new compounds designed to target a novel receptor site capable of producing analgesia without respiratory depression, physical dependence, reward behavior and minimal effects on gastrointestinal transit. We also propose to generate a series of agents designed to facilitate the study of this new target and other opioid mechanisms.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Rapaka, Rao
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New York
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Marrone, Gina F; Lu, Zhigang; Rossi, Grace et al. (2016) Tetrapeptide Endomorphin Analogs Require Both Full Length and Truncated Splice Variants of the Mu Opioid Receptor Gene Oprm1 for Analgesia. ACS Chem Neurosci 7:1717-1727
Marrone, Gina F; Grinnell, Steven G; Lu, Zhigang et al. (2016) Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS. Proc Natl Acad Sci U S A 113:3663-8
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Lu, Zhigang; Xu, Jin; Rossi, Grace C et al. (2015) Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. J Clin Invest 125:2626-30
Váradi, András; Marrone, Gina F; Eans, Shainnel O et al. (2015) Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior. ACS Chem Neurosci 6:1813-24
Marrone, Gina F; Majumdar, Susruta; Pasternak, Gavril W (2015) Radioligand Binding Assay for an Exon 11-Associated Mu Opioid Receptor Target. Methods Mol Biol 1335:241-9

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