Combinatorial lead optimization of a neuropeptide FF antagonist

L. Prokai, K. Prokai-Tatrai, A. Zharikova, X. Li, J. R. Rocca

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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 antiopioid 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.

Original languageEnglish
Pages (from-to)1623-1626
Number of pages4
JournalJournal of Medicinal Chemistry
Issue number10
StatePublished - 10 May 2001


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