Abstract

The objectives of the bioanalysis core are to measure the opioid receptor selectivity of the peptide analogues under development and evaluate their ability to reach CNS opioid receptors after peripheral administration. The procedures described are designed to allow the screening of a large number of analogues in a short period of time to prevent delays in the development cycle.
The specific aims are: 1. To measure the binding affinity of each of the analogues at mu, delta and kappa opioid receptors. Binding isotherms will be evaluated for multiple site interactions suggestive of the presence of opioid receptor subtypes. 2. To determine the in vitro potency of the analogues in the well characterized mouse vas deferens and guinea pig ileum bioassays. 3. To measure the ability of the analogues to cross membrane barriers both in vivo after parenteral administration and in vitro using a model of the mammalian blood brain barrier. The endpoint measured in the in vivo studies will be the induction of analgesia to a thermal stimulus while that measured in vitro will be the amount of analogues under study penetrating the model membrane barrier.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA006284-05
Application #
3775161
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of Arizona
Department
Type
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721

  Publications

Remesic, Michael; Macedonio, Giorgia; Mollica, Adriano et al. (2018) Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors. Bioorg Med Chem 26:3664-3667
Mowlazadeh Haghighi, Saghar; Zhou, Yang; Dai, Jixun et al. (2018) Replacement of Arg with Nle and modified D-Phe in the core sequence of MSHs, Ac-His-D-Phe-Arg-Trp-NH2, leads to hMC1R selectivity and pigmentation. Eur J Med Chem 151:815-823
Sandweiss, A J; McIntosh, M I; Moutal, A et al. (2018) Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential. Mol Psychiatry 23:1745-1755
Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita et al. (2017) Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. Pain 158:2386-2395
Vardanyan, Ruben S; Cain, James P; Haghighi, Saghar Mowlazadeh et al. (2017) Synthesis and Investigation of Mixed ?-Opioid and ?-Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain. J Heterocycl Chem 54:1228-1235
Cai, Minying; Marelli, Udaya Kiran; Mertz, Blake et al. (2017) Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists. Biochemistry 56:4201-4209
Remesic, Michael; Lee, Yeon Sun; Hruby, Victor J (2016) Cyclic Opioid Peptides. Curr Med Chem 23:1288-303
Ramos-Colon, Cyf N; Lee, Yeon Sun; Remesic, Michael et al. (2016) Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the ? Opioid Receptor. J Med Chem 59:10291-10298
Hall, Sara M; Lee, Yeon Sun; Hruby, Victor J (2016) Dynorphin A analogs for the treatment of chronic neuropathic pain. Future Med Chem 8:165-77
Deekonda, Srinivas; Cole, Jacob; Sunna, Sydney et al. (2016) Enkephalin analogues with N-phenyl-N-(piperidin-2-ylmethyl)propionamide derivatives: Synthesis and biological evaluations. Bioorg Med Chem Lett 26:222-7

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