Combinatorial lead optimization of a neuropeptide FF antagonist

被引:21
作者
Prokai, L [1 ]
Prokai-Tatrai, K
Zharikova, A
Li, XX
Rocca, JR
机构
[1] Univ Florida, Coll Pharm, Ctr Drug Discovery, Gainesville, FL 32610 USA
[2] Univ Florida, Coll Pharm, Ctr Neurobiol Aging, Gainesville, FL 32610 USA
[3] Univ Florida, McKnight Brain Inst, Gainesville, FL 32610 USA
关键词
D O I
10.1021/jm000512o
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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-GXR-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.
引用
收藏
页码:1623 / 1626
页数:4
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