Chin M H, Cioffi C L, Garay M, Neale R F, Shetty S S, DelGrande D, Mugrage B, Sills M A, Lipson K E
Ciba-Geigy Corporation, Research Department, Summit, New Jersey, USA.
J Pharmacol Exp Ther. 1996 Jan;276(1):74-83.
CGS 27830 [meso-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3- nitrophenyl)-3-pyridine carboxylic acid anhydride] is a nonpeptidic, insurmountable, endothelin (ET) receptor antagonist with approximately 10- to 20-fold selectivity for ETA receptors. CGS 27830 exhibits unusual binding properties which depend on the receptor and ligand: standard saturation binding experiments (coincubation of membranes with ligand in the absence or presence of antagonist) suggest that CGS 27830 is a competitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat cerebellar membranes (i.e., there was a change of apparent Kd with no change of maximum binding), but a noncompetitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat lung membranes (i.e., significant loss of total binding was observed). Although the antagonist appears to be a noncompetitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat lung membranes, CGS 27830 appears to be a competitive inhibitor of [125I]ET-1 binding to the same receptors as well as to ETA receptors in A7r5 cell membranes. Thus, CGS 27830 can distinguish [125I]IRL 1620 binding to ETB receptors in rat cerebellar and lung membranes, but not ET-1 binding to ETB receptors in these tissues. These unusual binding properties demonstrate that rat lung and cerebellum ETB receptors interact differently with IRL 1620 or ET-1.
CGS 27830[内消旋-1,4-二氢-5-甲氧基羰基-2,6-二甲基-4-(3-硝基苯基)-3-吡啶羧酸酐]是一种非肽类、不可克服的内皮素(ET)受体拮抗剂，对ETA受体具有约10至20倍的选择性。CGS 27830表现出不同寻常的结合特性，这取决于受体和配体：标准饱和结合实验(在不存在或存在拮抗剂的情况下将膜与配体共同孵育)表明，CGS 27830是[125I]IRL 1620与大鼠小脑膜中ETB受体结合的竞争性抑制剂(即，表观解离常数发生变化，最大结合量无变化)，但却是[125I]IRL 1620与大鼠肺膜中ETB受体结合的非竞争性抑制剂(即，观察到总结合量显著减少)。尽管该拮抗剂似乎是[125I]IRL 1620与大鼠肺膜中ETB受体结合的非竞争性抑制剂，但CGS 27830似乎是[125I]ET-1与相同受体以及A7r5细胞膜中ETA受体结合的竞争性抑制剂。因此，CGS 27830可以区分[125I]IRL 1620与大鼠小脑和肺膜中ETB受体的结合，但不能区分ET-1与这些组织中ETB受体的结合。这些不同寻常的结合特性表明，大鼠肺和小脑的ETB受体与IRL 1620或ET-1的相互作用不同。
