STRUCTURE-ACTIVITY-RELATIONSHIPS OF C-TERMINAL ENDOTHELIN HEXAPEPTIDE ANTAGONISTS

被引：55

作者：

DOHERTY, AM ^{[1
]}

CODY, WL ^{[1
]}

DEPUE, PL ^{[1
]}

HE, JX ^{[1
]}

WAITE, LA ^{[1
]}

LEONARD, DM ^{[1
]}

LEITZ, NL ^{[1
]}

DUDLEY, DT ^{[1
]}

RAPUNDALO, ST ^{[1
]}

HINGORANI, GP ^{[1
]}

HALEEN, SJ ^{[1
]}

LADOUCEUR, DM ^{[1
]}

HILL, KE ^{[1
]}

FLYNN, MA ^{[1
]}

REYNOLDS, EE ^{[1
]}

机构：

[1] WARNER LAMBERT PARKE DAVIS,PARKE DAVIS PHARMACEUT,DEPT SIGNAL TRANSDUCT & PHARMACOL,ANN ARBOR,MI 48105

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1993年 / 36卷 / 18期

关键词：

D O I：

10.1021/jm00070a001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of selective endothelin (ET) receptor antagonists will facilitate identification of the physiological and pathological roles for ET and its isopeptides. Structure-activity studies of the C-terminal hexapeptide of ET have been carried out to elucidate those amino acids important for receptor binding and agonist or antagonist activity. Binding studies were performed in rat heart ventricle, rabbit renal artery vascular smooth muscle cells, and rat cerebellum. In addition, many of the compounds have been evaluated functionally for their effects on endothelin-1-induced arachidonic acid release and inositol phosphate accumulation in specific cell lines. Selected compounds have been evaluated in a functional bioassay in tissue preparations specifically expressing either ET(A) or ET(B) receptors. We have previously described the structure-activity relationships in the hydrophobic C-terminal hexapeptide of ET, a region known to be highly important for receptor recognition. A mono-D-amino acid scan of the ET[16-21] revealed that substitution at His16 gave rise to analogs with significantly enhanced binding affinity. We have further evaluated the C-terminal region and will describe the design, synthesis, and pharmacological evaluation of several novel and potent ET peptide receptor antagonists.

引用

页码：2585 / 2594

页数：10

共 58 条

[51] A POTENT AND SPECIFIC AGONIST, SUC-[GLU9,ALA11,15]-ENDOTHELIN-1(8-21), IRL-1620, FOR THE ETB RECEPTOR [J].