The primary, long-term goals of the proposed research are: 1. The determination of the precise structural and conformational features required for ligand recognition at, mu, delta, and kappa opioid receptors. 2. The elucidation of those features which impart selectivity at individual opioid receptors, either through additional ligand-receptor interactions at the favored receptor or by impeding binding to the disfavored receptors. 3. The identification of those features that distinguish agonists from antagonists. and 4. The use of the information so gained for the design of high affinity agonists and antagonists selective for each of the three opioid receptors. The studies proposed here extend the approach used to develop a delta opioid receptor pharmacophore model to mu and kappa selective peptide leads developed in the current grant period as well as to peptidomimetic structures which represent possible leads to mu, delta, and kappa selective analogs. Prominent in the approach is the use of new methods for calculating structural models of the transmembrane domain of delta, mu, and kappa receptors (and G-protein coupled receptors, in general) to assist in the design of new opioid ligands and to complement experimental (NMR spectroscopy and x-ray diffraction) and theoretical (molecular mechanics calculations) conformational analysis of the ligands themselves. In addition to investigations directed toward the opioid receptors and their ligands, the design and synthesis of novel ligands for the opioid-related orphanin receptor (ORLI) will be pursued based upon analysis of combinatorial libraries and modeling of the orphanin receptor transmembrane domain. These studies will be done in collaboration with Richard Houghten of Torrey Pines Institute for Molecular Studies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003910-16
Application #
6378383
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hillery, Paul
Project Start
1985-08-01
Project End
2002-07-31
Budget Start
2001-04-15
Budget End
2002-07-31
Support Year
16
Fiscal Year
2001
Total Cost
$513,481
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Anand, Jessica P; Kochan, Kelsey E; Nastase, Anthony F et al. (2018) In vivo effects of ?-opioid receptor agonist/?-opioid receptor antagonist peptidomimetics following acute and repeated administration. Br J Pharmacol 175:2013-2027
Anand, Jessica P; Boyer, Brett T; Mosberg, Henry I et al. (2016) The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice. Psychopharmacology (Berl) 233:2479-87
Harland, Aubrie A; Bender, Aaron M; Griggs, Nicholas W et al. (2016) Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy ?-Opioid Receptor (MOR)/?-Opioid Receptor (DOR) Ligands. J Med Chem 59:4985-98
Bender, Aaron M; Griggs, Nicholas W; Anand, Jessica P et al. (2015) Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy ? opioid receptor/? opioid receptor ligands. ACS Chem Neurosci 6:1428-35
Geng, Jie; Pogozheva, Irina D; Mosberg, Henry I et al. (2015) Use of Functional Polymorphisms To Elucidate the Peptide Binding Site of TAP Complexes. J Immunol 195:3436-48
Harland, Aubrie A; Yeomans, Larisa; Griggs, Nicholas W et al. (2015) Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy ?-Opioid Receptor (MOR) Agonists/?-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities. J Med Chem 58:8952-69
Kumar, Vinod; Ridzwan, Irna E; Grivas, Konstantinos et al. (2014) Selectively promiscuous opioid ligands: discovery of high affinity/low efficacy opioid ligands with substantial nociceptin opioid peptide receptor affinity. J Med Chem 57:4049-57
Anand, Jessica P; Porter-Barrus, Vanessa R; Waldschmidt, Helen V et al. (2014) Translation of structure-activity relationships from cyclic mixed efficacy opioid peptides to linear analogues. Biopolymers 102:107-14
Mosberg, Henry I; Yeomans, Larisa; Anand, Jessica P et al. (2014) Development of a bioavailable ? opioid receptor (MOPr) agonist, ? opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance. J Med Chem 57:3148-53
Bender, Aaron M; Clark, Mary J; Agius, Michael P et al. (2014) Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity ? opioid receptor (MOR) agonist/? opioid receptor (DOR) antagonist ligands. Bioorg Med Chem Lett 24:548-51

Showing the most recent 10 out of 83 publications