PMID: 11334572May 4, 2001Paper

Combinatorial lead optimization of a neuropeptide FF antagonist

Journal of Medicinal Chemistry
Laszlo ProkaiJ R Rocca

Abstract

The tripeptide Pro-Gln-Arg-NH2, derivatized at the secondary amino group of the proline residue with 5-(dimethylamino)-1-naphthalenesulfonyl (dansyl-PQR-NH2), antagonizes the central anti-opioid action of neuropeptide FF in animals after systemic administration and, therefore, is a therapeutic lead to treat opiate withdrawal. For a combinatorial optimization to improve potency, libraries focused on the possible replacement of the proline and glutamine residues of this lead compound were obtained by a solid-phase split-and-mix method using coded amino acids (excluding cysteine) as building blocks. After screening for competitive binding against a radioiodinated neuropeptide FF analogue, 5-(dimethylamino)-1-naphthalenesulfonyl-Gly-Ser-Arg-NH2 (dansyl-GSR-NH2) has emerged as one of the compounds in the library with high affinity to the NPFF receptor and even with a moderate increase compared to dansyl-PQR-NH2 in its predicted ability to penetrate the central nervous system.

References

Feb 17, 1995·Journal of Medicinal Chemistry·C PidgeonL Glunz
Nov 22, 1996·Journal of Medicinal Chemistry·K Prokai-TatraiN Bodor
Oct 3, 1999·Journal of Medicinal Chemistry·R A HoughtenJ M Ostresh
Dec 2, 1999·Journal of Medicinal Chemistry·L ProkaiN Bodor
Jun 14, 2000·The Journal of Biological Chemistry·N A ElshourbagyH M Sarau
Aug 10, 2000·Medicinal Research Reviews·L ProkaiN Bodor
Oct 12, 2000·The Journal of Biological Chemistry·J A BoniniB Borowsky

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Citations

Feb 24, 2006·Peptides·Laszlo ProkaiKatalin Prokai-Tatrai
Dec 18, 2001·Journal of Mass Spectrometry : JMS·L ProkaiK Prokai-Tatrai
Apr 1, 2010·The Journal of Pharmacology and Experimental Therapeutics·Jelveh LamehLuis R Gardell

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