AMPA受体激动剂：（+）-（S）-和（-）-（R）-2-氨基-3-[3-羟基-5-（2-吡啶基）-异恶唑-4-基]-丙酸（2-Py-AMPA）的拆分、构型确定及药理学研究

AMPA receptor agonists: resolution, configurational assignment, and pharmacology of (+)-(S)- and (-)-(R)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-isoxazol-4-yl]-propionic acid (2-Py-AMPA).

作者信息

Johansen T N, Ebert B, Falch E, Krogsgaard-Larsen P

机构信息

Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.

出版信息

Chirality. 1997;9(3):274-80. doi: 10.1002/(SICI)1520-636X(1997)9:3<274::AID-CHIR12>3.0.CO;2-K.

DOI:10.1002/(SICI)1520-636X(1997)9:3<274::AID-CHIR12>3.0.CO;2-K

PMID:9176992

Abstract

We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonist and (R)-APPA a weak competitive AMPA receptor antagonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee > or = 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [3H]AMPA binding (IC50 = 0.19 +/- 0.06 microM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC50 = 4.5 +/- 0.3 microM) comparable with AMPA (IC50 = 0.040 +/- 0.01 microM; EC50 = 3.5 +/- 0.2 microM), but much more potent than (+)-(S)-APPA (IC50 = 5.5 +/- 2.2 microM; EC50 = 230 +/- 12 microM). Like (-)-(R)-APPA (IC50 > 100 microM), (-)-(R)-2-Py-AMPA (IC50 > 100 microM) did not significantly affect [3H]AMPA binding, and both compounds were weak AMPA receptor antagonists (Ki = 270 +/- 50 and 290 +/- 20 microM, respectively).

摘要

我们之前已经表明，（RS）-2-氨基-3-（3-羟基-5-苯基异恶唑-4-基）丙酸（APPA）在（RS）-2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸（AMPA）受体上表现出部分激动剂的特性，而（S）-APPA是一种完全的AMPA受体激动剂，（R）-APPA是一种弱竞争性AMPA受体拮抗剂。这一观察结果促使我们引入了新的药理学概念——功能性部分激动作用。最近我们发现，APPA的2-吡啶基类似物，（RS）-2-氨基-3-[3-羟基-5-（2-吡啶基）异恶唑-4-基]丙酸（2-Py-AMPA），是一种强效且明显完全的AMPA受体激动剂，并且该化合物现已通过使用Chirobiotic T柱的手性高效液相色谱法拆分为（+）-和（-）-2-Py-AMPA（对映体过量≥99.0%）。APPA对映体的绝对立体化学先前已通过X射线分析确定，并且基于对APPA和2-Py-AMPA对映体圆二色光谱的比较研究，分别将（+）-和（-）-2-Py-AMPA指定为（S）-和（R）-构型。在一系列受体结合研究中，2-Py-AMPA的两种对映体对海人藻酸受体位点或N-甲基-D-天冬氨酸（NMDA）受体复合物的不同位点均未显示出可检测到的亲和力。（+）-（S）-2-Py-AMPA是[3H]AMPA结合的有效抑制剂（IC50 = 0.19±0.06微摩尔），并且在大鼠皮质楔形制剂中是一种强效的AMPA受体激动剂（EC50 = 4.5±0.3微摩尔），与AMPA相当（IC50 = 0.040±0.01微摩尔；EC50 = 3.5±0.2微摩尔），但比（+）-（S）-APPA（IC50 = 5.5±2.2微摩尔；EC50 = 230±12微摩尔）强效得多。与（-）-（R）-APPA（IC50＞100微摩尔）一样，（-）-（R）-2-Py-AMPA（IC50＞100微摩尔）对[3H]AMPA结合没有显著影响，并且这两种化合物均为弱AMPA受体拮抗剂（Ki分别为270±50和290±20微摩尔）。