Madsen U, Sløk F A, Stensbøl T B, Bräuner-Osborne H, Lützhøft H H, Poulsen M V, Eriksen L, Krogsgaard-Larsen P
NeuroScience PharmaBiotec Centre, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100, Copenhagen, Denmark.
Eur J Med Chem. 2000 Jan;35(1):69-76. doi: 10.1016/s0223-5234(00)00104-5.
We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). Using these AMPA receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA receptors. The synthesized compounds have been tested for activity at ionotropic excitatory amino acid (EAA) receptors using receptor binding and electrophysiological techniques, and for activity at metabotropic EAA receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2), on the other hand, was shown to be a selective AMPA receptor antagonist (IC(50) = 73 microM), more potent in electrophysiological experiments than AMOA (IC(50) = 320 microM). The isomeric analogue of 2, compound 5, did not show AMPA antagonist effects, but was a weak NMDA receptor antagonist (IC(50) = 540 microM). Finally, compound 3, which is an isomer of ACPA, turned out to be a very weak NMDA antagonist, and an AMPA receptor agonist approximately 1000 times weaker than ACPA. None of the compounds showed agonist or antagonist effects at metabotropic EAA receptors.
我们之前已描述过强效且具选择性的（RS）-2-氨基-3-（3-羟基-5-甲基-4-异恶唑基）丙酸（AMPA）受体激动剂（RS）-2-氨基-3-（3-羧基-5-甲基-4-异恶唑基）丙酸（ACPA）以及AMPA受体拮抗剂（RS）-2-氨基-3-[3-（羧基甲氧基）-5-甲基-4-异恶唑基]丙酸（AMOA）。以这些AMPA受体配体为先导物，已开发出一系列化合物作为工具，用于进一步阐明AMPA受体激活和阻断的结构要求。已使用受体结合和电生理技术测试了合成化合物对离子型兴奋性氨基酸（EAA）受体的活性，并使用第二信使测定法测试了其对代谢型EAA受体的活性。化合物1和4基本无活性。另一方面，（RS）-2-氨基-3-[3-（2-羧乙基）-5-甲基-4-异恶唑基]丙酸（ACMP，2）被证明是一种选择性AMPA受体拮抗剂（IC（50）= 73 microM），在电生理实验中比AMOA（IC（50）= 320 microM）更有效。2的异构体类似物化合物5未表现出AMPA拮抗剂作用，但却是一种弱NMDA受体拮抗剂（IC（50）= 540 microM）。最后，化合物3是ACPA的异构体，结果证明是一种非常弱的NMDA拮抗剂，并且是一种比ACPA弱约1000倍的AMPA受体激动剂。这些化合物均未在代谢型EAA受体上表现出激动剂或拮抗剂作用。
