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)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York
United States
Zip Code
Xu, Jin; Xu, Mingming; Bolan, Elizabeth et al. (2014) Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P. Synapse 68:144-52
Xu, Jin; Lu, Zhigang; Xu, Mingming et al. (2014) A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the ? opioid receptor gene OPRM1 via hnRNPH interactions. J Neurosci 34:11048-66
Kim, Charles; Barbut, Denise; Heinemann, Murk H et al. (2014) Synthetic neurotensin analogues are nontoxic analgesics for the rabbit cornea. Invest Ophthalmol Vis Sci 55:3586-93
Pasternak, Gavril W (2014) Opiate pharmacology and relief of pain. J Clin Oncol 32:1655-61
Lu, Zhigang; Xu, Jin; Xu, Mingming et al. (2014) Morphine regulates expression of *-opioid receptor MOR-1A, an intron-retention carboxyl terminal splice variant of the *-opioid receptor (OPRM1) gene via miR-103/miR-107. Mol Pharmacol 85:368-80
Xu, Jin; Lu, Zhigang; Xu, Mingming et al. (2014) Differential expressions of the alternatively spliced variant mRNAs of the µ opioid receptor gene, OPRM1, in brain regions of four inbred mouse strains. PLoS One 9:e111267
Váradi, András; Palmer, Travis C; Notis, Paula R et al. (2014) Three-component coupling approach for the synthesis of diverse heterocycles utilizing reactive nitrilium trapping. Org Lett 16:1668-71
Grinnell, Steven G; Majumdar, Susruta; Narayan, Ankita et al. (2014) Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA. J Pharmacol Exp Ther 350:710-8
Pasternak, Gavril W (2014) Opioids and their receptors: Are we there yet? Neuropharmacology 76 Pt B:198-203
Su, Wendy; Pasternak, Gavril W (2013) The role of multidrug resistance-associated protein in the blood-brain barrier and opioid analgesia. Synapse 67:609-19

Showing the most recent 10 out of 52 publications