Ahmadian H, Nielsen B, Bräuner-Osborne H, Johansen T N, Stensbøl T B, Sløk F A, Sekiyama N, Nakanishi S, Krogsgaard-Larsen P, Madsen U
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
J Med Chem. 1997 Oct 24;40(22):3700-5. doi: 10.1021/jm9703597.
Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu6 (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the "Ugi four-component condensation", 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0% ee) through several crystallizations. 6 (99.7% ee) and 7 (99.9% ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on 1H NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM).
我们之前的出版物（《药物化学杂志》1996年，第39卷，3188 - 3194页）将（RS）-2-氨基-4-（3-羟基-5-甲基异恶唑-4-基）丁酸（同型AMPA）描述为代谢型兴奋性氨基酸（EAA）受体mGlu6亚型的高选择性激动剂。同型AMPA已经成为mGlu6药理学特性研究的标准激动剂（《药理学趋势增刊》1997年，第37 - 39页），我们在此报告（S）-（6）和（R）-（7）同型AMPA的拆分、构型确定及药理学研究。利用“乌吉四组分缩合反应”，3-（3-乙氧基-5-甲基异恶唑-4-基）丙醛（10）分别生成了可分离的6和7的非对映体衍生物，即化合物12和11。12经一步或两步脱保护得到大量外消旋化的6，通过多次结晶以低产率将其转化为6（对映体过量99.0%）。最终通过制备型手性高效液相色谱法得到了6（对映体过量99.7%）和7（对映体过量99.9%）。6和7的构型确定分别基于对12和11的1H NMR光谱研究以及对6和7的圆二色性研究。使用不同溶剂的旋光度值以及6和7的手性高效液相色谱洗脱顺序支持了光谱构型确定的结果。研究了6和7对离子型EAA（iGlu）受体以及mGlu1 - 7的活性。（S）-同型AMPA（6）被证明是mGlu6的特异性激动剂（EC50 = 58 ± 11 μM），其效力与内源性mGlu激动剂（S）-谷氨酸（EC50 = 20 ± 3 μM）相当。尽管同型AMPA对iGlu受体未显示出显著影响，但在mGlu1 - 7上无活性的（R）-同型AMPA（7）结果却是一种弱的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂（IC50 = 131 ± 18 μM）。
