NG-Acyl-argininamides as NPY Y1 receptor antagonists: Influence of structurally diverse acyl substituents on stability and affinity

被引：27

作者：

Weiss, Stefan ^{[1
]}

Keller, Max ^{[2
]}

Bernhardt, Guenther ^{[2
]}

Buschauer, Armin ^{[2
]}

Koenig, Burkhard ^{[1
]}

机构：

[1] Univ Regensburg, Inst Organ Chem, D-93040 Regensburg, Germany

[2] Univ Regensburg, Inst Pharm, D-93040 Regensburg, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 17期

关键词：

Acyl guanidines; NPY; BIBP; 3226; GPCR; HISTAMINE H-2-RECEPTOR AGONISTS; NEUROPEPTIDE-Y; HIGHLY POTENT; IMIDAZOLYLPROPYLGUANIDINES; PHARMACOLOGY; GUANIDINES; INHIBITION; REACTIVITY; LIGANDS; ROUTE;

D O I：

10.1016/j.bmc.2010.07.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

N-G-Acylated argininamides, covering a broad range of lipophilicity (calculated log D values: -1.8-12.5), were synthesized and investigated for NPY Y-1 receptor (Y1R) antagonism, Y1R affinity and stability in buffer (N-G-deacylation, yielding BIBP 3226). Broad structural variation of substituents was tolerated. The K-i (binding) and K-b values (Y1R antagonism) varied from low nM to one-digit mu M. Most of the compounds proved to be sufficiently stable at pH 7.4 over 90 min to determine reliable pharmacological data in vitro. Exceptionally high instability was detected when a succinyl moiety was attached to the guanidine, probably, due to an intramolecular cleavage mechanism. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：6292 / 6304

页数：13

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