Project Details


The mammalian octapeptide FLQPQRFamide (F8Fa, neuropeptide FF, NPFF) an
"anti-opioid" peptide, plays a role in opiate dependence and subsequent
abstinence syndrome. An antagonist of this peptide may, therefore,
alleviate opioid tolerance and dependence, and allow for the management of
opiate abstinence syndrome. The peptide antagonist used as a lead compound
does not reach the central nervous system (CNS) after systemic
administration, because it is lipid-insoluble and unable to penetrate the
blood-brain barrier. The objective is to develop such antagonists that can
be administered parenterally (by i.v. injection, subcutaneously, etc.),
and transport the pharmacologically active agents into the CNS (chemical
delivery systems, CDSs). A neuropeptide FF antagonist daYFLQPQRa (daY8Ra,
an N-terminal desaminotyrosine-blocked peptide amide containing the 1-7
residues of F8Fa) was used as a lead compound to design CDSs that renders
the peptide lipid-soluble in order to enhance access to the CNS by passive
transport, and allow enzymatic conversions within the CNS at the attached
functional groups to prevent the peptide from leaving the CNS after
delivery. Finally, the active antagonist is released by sequential
metabolism. Analogs of daY8Ra will also be designed by a) removing the
FLFQ segment from day8ra, b) by replacing the N-terminal desaminotyrosine
(daY) of daY8Ra with an N-alkylated nicotinamide residue to eliminate the
need for an activating step, and c) by combining a and b. The compounds
will be synthesized by solid and solution-phase syntheses based on the
sequential elongation of the peptide chain, then coupling appropriate
peptide segments that possess the desired targeting and protecting
functional groups. In vitro stability/metabolism studies will be used to
confirm the occurrence of the designed metabolic changes and to
investigate metabolic changes and to investigate metabolic properties
crucial to the sequential bioactivation involved in CNS-targeting CNS-
uptake and retention of the CDSs after i.v. injection of the CDSs to rats
will be evaluated by measuring the concentration of the antagonist and its
precursor(s) in brain tissue as a function of time. Pharmacological
evaluation of the brain-targeted NPFF antagonists will include the quasi-
morphine abstinence syndrome (QMAS) induced by i.c.v. NPFF in rats, and
CNS-targeting of pharmacologically significant amount of NPFF antagonist
by the CDS approach will be assessed by using the abstinence syndrome
participated by naloxone in morphine-dependent rats as a paradigm. Teeth
chattering/chewing, writhes/grasps, shakes and tremors, and ptosis as
measures of the QMAS and naloxone-participated abstinence will be recorded
for groups of animals, and the effect of the compounds will be
statistically evaluated. Based on the attenuation of abstinence syndromes,
metabolic stability data, and CNS-distribution studies, candidates will be
selected for further structure-based design, biochemical, pharmaceutical
and pharmacological studies that continue preclinical development of these
potential new drugs.
Effective start/end date9/07/9830/06/00


  • National Institute on Drug Abuse
  • National Institute on Drug Abuse


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