Madsen U, Wong E H
Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
J Med Chem. 1992 Jan;35(1):107-11. doi: 10.1021/jm00079a013.
The novel acidic amino acids 6a-c, 7, and 8 have been synthesized via 1,3-dipolar cycloadditions, using nitrile oxides and alkynes. The prepared compounds are heterocyclic analogues of glutamic acid with differing chain lengths. One of these compounds, (RS)-2-amino-3-(3-carboxy-5-methyl-4- isoxazolyl)propionic acid (ACPA, 8), was shown in [3H]AMPA binding studies to be more active than AMPA itself (IC50 = 20 nM compared to IC50 = 79 nM for AMPA). No affinity for NMDA receptors (NMDA-sensitive [3H]glutamic acid binding) was found, and only weak affinity in [3H]kainic acid binding (IC50 = 6.3 microM) was detected. The excitatory activity in rat cortical wedge also showed that ACPA was more potent than AMPA (EC50 = 1.0 microM compared to EC50 = 3.5 microM for AMPA). The depolarizing effect of ACPA could be fully antagonized by the selective non-NMDA antagonist 6-cyano-7-nitro-quinoxazoline-2,3-dione (CNQX), but was unaffected by the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (AP5).
新型酸性氨基酸6a - c、7和8已通过1,3 - 偶极环加成反应，利用腈氧化物和炔烃合成。所制备的化合物是链长不同的谷氨酸杂环类似物。其中一种化合物，(RS)-2 - 氨基 - 3-(3 - 羧基 - 5 - 甲基 - 4 - 异恶唑基)丙酸（ACPA，8），在[³H]AMPA结合研究中显示比AMPA本身更具活性（IC50 = 20 nM，而AMPA的IC50 = 79 nM）。未发现对NMDA受体有亲和力（NMDA敏感的[³H]谷氨酸结合），并且在[³H]海人酸结合中仅检测到弱亲和力（IC50 = 6.3 μM）。在大鼠皮质楔形组织中的兴奋活性也表明ACPA比AMPA更有效（EC50 = 1.0 μM，而AMPA的EC50 = 3.5 μM）。ACPA的去极化作用可被选择性非NMDA拮抗剂6 - 氰基 - 7 - 硝基 - 喹喔啉 - 2,3 - 二酮（CNQX）完全拮抗，但不受选择性NMDA拮抗剂D - 2 - 氨基 - 5 - 膦酰戊酸（AP5）的影响。
