[H-3] CGP-39653 - A NEW N-METHYL-D-ASPARTATE ANTAGONIST RADIOLIGAND WITH LOW NANOMOLAR AFFINITY IN RAT-BRAIN
[H-3] CGP-39653 - A NEW N-METHYL-D-ASPARTATE ANTAGONIST RADIOLIGAND WITH LOW NANOMOLAR AFFINITY IN RAT-BRAIN
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DOI：
10.1016/0014-2999(91)90063-v
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发表时间：
1991-01-03
影响因子：
5
通讯作者：
WILLIAMS, M
中科院分区：
文献类型：
--
作者：
SILLS, MA;FAGG, G;WILLIAMS, M
最初发现CGP 39653（D，L-（E）-2-氨基-4-丙基-5-膦酰基-3-戊烯酸）可抑制[H-3] L-谷氨酸和[H-3]3-（（+/-）2-羧基哌嗪-4-基）-丙基-1-膦酸（[H-3]CPP）的结合，K（i）值分别为230和5 nM。 放射性标记化合物[H-3]CGP 39653以可饱和和可逆的方式与大鼠额叶皮质膜结合。 饱和实验的分析表明，配体标记一个结合位点，K（d）值为6 nM。 竞争实验表明，一些竞争性兴奋性氨基酸激动剂和拮抗剂化合物的效力顺序与先前发现的其他N-甲基-D-天冬氨酸（NMDA）受体配体相似。 在这些竞争性抑制剂，产生陡峭的抑制曲线，甘氨酸抑制结合在一个复杂的方式。 当探索未标记化合物的功能活性时，CGP 39653在体外阻断大鼠皮质楔中NMDA诱发的去极化，并抑制皮质膜中L-谷氨酸刺激的[H-3]N（1-[2-噻吩基]环己基）3，4-哌啶（[H-3]TCP）结合。 这些结果表明，[H-3]CGP 39653作为高亲和力拮抗剂选择性结合NMDA受体，是目前标记NMDA受体的首选配体。
CGP 39653 (D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) was initially discovered to inhibit the binding of [H-3]L-glutamate and [H-3]3-((+/-)2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ([H-3]CPP) with K(i) values of 230 and 5 nM, respectively. The radiolabeled compound [H-3]CGP 39653 binds to rat frontal cortical membranes in a saturable and reversible manner. Analysis of saturation experiments revealed that the ligand labels one binding site with a K(d) value of 6 nM. Competition experiments indicated that the order of potency of a number of competitive excitatory amino acid agonist and antagonist compounds was similar to that found previously for other N-methyl-D-aspartate (NMDA) receptor ligands. In contrast to these competitive inhibitors, which produced steep inhibition curves, glycine inhibited binding in a complex manner. When the functional activity of the unlabeled compound was explored, CGP 39653 blocked NMDA-evoked depolarizations in the rat cortical wedge in vitro and inhibited L-glutamate stimulated [H-3]N(1-[2-thienyl]cyclohexyl)3,4-piperidine ([H-3]TCP) binding in cortical membranes. These results suggest that [H-3]CGP 39653 selectively binds to the NMDA receptor as an antagonist with high affinity and is currently the ligand of choice for labeling the NMDA receptor.