This project is part of a Program Project that is a collective research effort todesign highly selective opioid receptor peptide or peptidomimetic ligands for the nonaddictive treatment of pain and drug dependency. The objective of this project is to elucidate which molecular characteristics of opioid receptor ligands may be modified to increase their passive transport from the blood to receptor sites in the brain. This necessarily involves permeation through biological membranes that compose the blood-brain barrier. In order to understand the passive permeation of these ligands through membrans we have adopted a biophysical approach to analyze the permeation in terms of the water-to-membrane partition, transmembrane diffusion, and membrane-water interfacial interactions. These studies include both (1) the determination of the rate of peptide permeation as a fuction of the peptide structure and the membrane composition; and (2) the characterization of the thermodynamics of ligand transfer from water to the membrane. The later includes the determination of partition coefficients via an equililbrium dialysis procedure developed (in this project) for these peptides, and isothermal titration calorimetry to directly measure the enthalpy of peptide-membrane binding. Taken together these data provide the necessary information to ascertain which elements of the peptide ligand may be usefully modified to enhance its membrane permeation. The above results will be correlated with molecular structural information (from NMR and computatinal studies in other projects of this Program Project) to design new opioid ligands that amplify the effective modes of transfer across membranes. The two major classes of opioid teceptor peptides that have been studied to data are the highly selrctive delta receptor ligand, DPDPE and its analogs, and the potenti analgesic, biphalin and its analogs. Future studies will include new modifications of these two peptides, as well as prodrugs of this peptides, new cyclic and acyclic deltorphins, and other peptides and peptidomimetics proposed in Project 0001 that prove to be especially bioactive.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA006284-11
Application #
6300721
Study Section
Project Start
2000-04-01
Project End
2001-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
11
Fiscal Year
2000
Total Cost
$104,534
Indirect Cost
Name
University of Arizona
Department
Type
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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
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
Lee, Yeon Sun; Kupp, Robert; Remesic, Michael V et al. (2016) Various modifications of the amphipathic dynorphin A pharmacophore for rat brain bradykinin receptors. Chem Biol Drug Des 88:615-9
Hall, Sara M; LeBaron, Lindsay; Ramos-Colon, Cyf et al. (2016) Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain. ACS Chem Neurosci 7:1746-1752

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