Bräuner-Osborne H, Sløk F A, Skjaerbaek N, Ebert B, Sekiyama N, Nakanishi S, Krogsgaard-Larsen P
PharmaBiotec Research Center, Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
J Med Chem. 1996 Aug 2;39(16):3188-94. doi: 10.1021/jm9602569.
The homologous series of acidic amino acids, ranging from aspartic acid (1) to 2-aminosuberic acid (5), and the corresponding series of 3-isoxazolol bioisosteres of these amino acids, ranging from (RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA, 6) to (RS)-2-amino-6-(3-hydroxy-5-methylisoxazol-4-yl)hexanoic acid (10), were tested as ligands for metabotropic excitatory amino acid receptors (mGlu1 alpha, mGlu2, mGlu4a, and mGlu6). Whereas AMAA (6) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propinoic acid (AMPA, 7) are potent and highly selective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors, respectively, the higher homologue of AMPA (7), (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (homo-AMPA, 8), is inactive at ionotropic excitatory amino acid receptors. Homo-AMPA (8), which is a 3-isoxazolol bioisostere of 2-aminoadipic acid (3), was, however, shown to be a specific and rather potent agonist at mGlu6, approximately 4 times weaker than the nonselective excitatory amino acid receptor agonist (S)-glutamic acid. 2-Aminoadipic acid (3), which shows a complex excitatory amino acid synaptic pharmacology, was an agonist at mGlu6 as well as mGlu2. AMPA (7) and the higher homologue of homo-AMPA (8), (RS)-2-amino-5-(3-hydroxy-5-methylisoxazol-4-yl)pentanoic acid (9), showed relatively weak agonist effects at mGlu6. It is concluded that homo-AMPA (8) is likely to be a useful tool for studies of the pharmacology and physiological role of mGlu6. We describe a new versatile synthesis of this homologue of AMPA and the synthesis of compound 10.
对酸性氨基酸的同系物（从天冬氨酸（1）到2-氨基辛二酸（5））以及这些氨基酸相应的3-异恶唑醇生物电子等排体同系物（从（RS）-2-氨基-2-（3-羟基-5-甲基异恶唑-4-基）乙酸（AMAA，6）到（RS）-2-氨基-6-（3-羟基-5-甲基异恶唑-4-基）己酸（10））进行了测试，以确定它们作为代谢型兴奋性氨基酸受体（mGlu1α、mGlu2、mGlu4a和mGlu6）配体的活性。尽管AMAA（6）和（RS）-2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸（AMPA，7）分别是N-甲基-D-天冬氨酸（NMDA）受体和AMPA受体的强效且高度选择性激动剂，但AMPA（7）的更高同系物（RS）-2-氨基-4-（3-羟基-5-甲基异恶唑-4-基）丁酸（高同系物AMPA，8）对离子型兴奋性氨基酸受体无活性。然而，高同系物AMPA（8）是2-氨基己二酸（3）的3-异恶唑醇生物电子等排体，已证明它是mGlu6的特异性且相当强效的激动剂，效力约为非选择性兴奋性氨基酸受体激动剂（S）-谷氨酸的1/4。2-氨基己二酸（3）表现出复杂的兴奋性氨基酸突触药理学特性，它是mGlu6以及mGlu2的激动剂。AMPA（7）和高同系物AMPA（8）的更高同系物（RS）-2-氨基-5-（3-羟基-5-甲基异恶唑-4-基）戊酸（9）在mGlu6上表现出相对较弱的激动剂作用。得出的结论是，高同系物AMPA（8）可能是研究mGlu6药理学和生理作用的有用工具。我们描述了这种AMPA同系物的一种新的通用合成方法以及化合物（RS）-2-氨基-6-（3-羟基-5-甲基异恶唑-4-基）己酸（10）的合成方法。
