In this grant we plan to capitalize on our past progress and success by describing the mechanism by which opioid peptide drugs entry into the central nervous system. We will also determine the A.D.M.E. and optimal route of delivery of various peptide analogues including biphalin.
Our specific aims are centered on our hypothesis that there are specific uptake systems for peptide analogues at the blood-brain and /or blood-CSF barriers.
There specific aims i nclude our goal to: 1. Determine if the BBB or blood-CSF barrier is the predominate route of opioid entry into the CNS. 2. Determine if CNS uptake of opioid peptide drugs is by a process of diffusion or saturable transport and examine the kinetics of these uptake systems. 3. Examine if these opioid drugs use the already identified uptake systems to enter the CNS. Is it by absorptive-mediated endocytosis, receptor mediated transport or carrier mediated transport? 4. What role do the amino acid, monocarboxylic acid, nucleoside and hexose transporters play in transporting opioid peptide drugs across the blood-brain and blood-CSF barriers? 5. Does halogenation affect the diffusion and/or saturable uptake properties of opioid peptide drugs? 6. Examine the uptake of opioid peptide drug ligands into specific regions of the CNS as related to the density of opioid binding sites. 7. Does the use of colloidal polymer particles (nanoparticles) improve passage of peptide drugs into the CNS? 8. When placed in vivo, what is the effect of the route of administration on the whole body biodistribution (ADME) of opioid peptide drugs? Since we have already shown that specific modifications of peptide design lead to dramatic improvements in drug stability and CNS uptake, we are confident that we can continue to use our integrated, analytical, enzymatic, metabolic, biodistribution and in situ blood-brain barrier technique to describe the predominant route and mechanism by which to delivery opioid peptide drugs to the CNS.
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