Combinatorial lead optimization of a neuropeptide FF antagonist

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 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
Volume44
Issue number10
DOIs
StatePublished - 10 May 2001

Fingerprint

Proline
Libraries
Opiate Alkaloids
Competitive Binding
Glutamine
Cysteine
Central Nervous System
Amino Acids
Lead
argininamide
phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide
Therapeutics
neuropeptide FF receptor
serinamide

Cite this

Prokai, L. ; Prokai-Tatrai, K. ; Zharikova, A. ; Li, X. ; Rocca, J. R. / Combinatorial lead optimization of a neuropeptide FF antagonist. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 10. pp. 1623-1626.
@article{9a4651ff29264cf195e85764a1b0953b,
title = "Combinatorial lead optimization of a neuropeptide FF antagonist",
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 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.",
author = "L. Prokai and K. Prokai-Tatrai and A. Zharikova and X. Li and Rocca, {J. R.}",
year = "2001",
month = "5",
day = "10",
doi = "10.1021/jm000512o",
language = "English",
volume = "44",
pages = "1623--1626",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "10",

}

Combinatorial lead optimization of a neuropeptide FF antagonist. / Prokai, L.; Prokai-Tatrai, K.; Zharikova, A.; Li, X.; Rocca, J. R.

In: Journal of Medicinal Chemistry, Vol. 44, No. 10, 10.05.2001, p. 1623-1626.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Combinatorial lead optimization of a neuropeptide FF antagonist

AU - Prokai, L.

AU - Prokai-Tatrai, K.

AU - Zharikova, A.

AU - Li, X.

AU - Rocca, J. R.

PY - 2001/5/10

Y1 - 2001/5/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035837074&partnerID=8YFLogxK

U2 - 10.1021/jm000512o

DO - 10.1021/jm000512o

M3 - Article

C2 - 11334572

AN - SCOPUS:0035837074

VL - 44

SP - 1623

EP - 1626

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 10

ER -