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Combinatorial lead optimization of a neuropeptide FF antagonist
L Prokai1, K Prokai-Tatrai, A Zharikova
1Center for Drug Discovery, College of Pharmacy, and The McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. lprokai@grove.ufl.edu
Journal of Medicinal Chemistry
|May 4, 2001
Summary
Researchers developed a new compound, dansyl-GSR-NH2, to treat opiate withdrawal. This compound shows high affinity for the NPFF receptor and improved central nervous system penetration compared to previous leads.
Area of Science:
- Neuropharmacology
- Medicinal Chemistry
Background:
- Neuropeptide FF (NPFF) plays a role in the central anti-opioid system.
- The tripeptide Pro-Gln-Arg-NH2 (dansyl-PQR-NH2) antagonizes NPFF's central action, showing therapeutic potential for opiate withdrawal.
Purpose of the Study:
- To optimize the potency and central nervous system (CNS) penetration of dansyl-PQR-NH2.
- To identify novel NPFF receptor antagonists for treating opiate withdrawal.
Main Methods:
- Solid-phase split-and-mix synthesis of peptide libraries.
- Combinatorial chemistry using coded amino acids to replace proline and glutamine residues.
- Competitive binding assays using a radioiodinated NPFF analogue to screen for receptor affinity.
Main Results:
- A library of dansyl-peptamide analogues was synthesized.
- 5-(dimethylamino)-1-naphthalenesulfonyl-Gly-Ser-Arg-NH2 (dansyl-GSR-NH2) exhibited high affinity for the NPFF receptor.
- Dansyl-GSR-NH2 demonstrated a moderate increase in predicted CNS penetration compared to dansyl-PQR-NH2.
Conclusions:
- Dansyl-GSR-NH2 is a promising therapeutic lead for opiate withdrawal treatment.
- The modified peptide structure enhances NPFF receptor binding and CNS penetration.