Skjaerbaek N, Brehm L, Johansen T N, Hansen L M, Nielsen B, Ebert B, Søby K K, Stensbøl T B, Falch E, Krogsgaard-Larsen P
PharmaBiotec Research Centre, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark.
Bioorg Med Chem. 1998 Jan;6(1):119-31. doi: 10.1016/s0968-0896(97)10017-7.
We have previously shown that (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA, 2) is a functional partial agonist at the (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors, reflecting that (S)-APPA is a full agonist and (R)-APPA a competitive antagonist at AMPA receptors. We have now synthesized and pharmacologically characterized (RS)-2-amino-3-[3-hydroxy-5-(2-fluorophenyl)isoxazol-4-yl]propioni c acid (2-F-APPA, 5a), 3-F-APPA (5b), 4-F-APPA (5c), (S)-4-F-APPA (6), (R)-4-F-APPA (7), and the fully and partially, respectively, saturated APPA (2) analogues, (RS)-2-amino-3-(3-hydroxy-5-cyclohexylisoxazol-4-yl)propionic acid (5d) and compound 5e containing a 1-cyclohexenyl ring. The absolute stereochemistry of 6 and 7 was established on the basis of comparative circular dichroism studies on 6, 7, and (S)- and (R)-APPA. 4-F-APPA (5c), (S)-4-F-APPA (6), 5d, and 5e were shown to selectively inhibit [3H]AMPA binding and to activate AMPA receptors. Whereas (S)-4-F-APPA (6) showed full AMPA receptor agonism, (R)-4-F-APPA (7) was an AMPA receptor antagonist. Co-administration of (S)- and (R)-4-F-APPA to the rat cortical wedge preparation produced functional partial AMPA receptor agonism. Semi empirical calculations showed that the magnitude of the torsional angle of the bond connecting the two rings in the series of nonannulated bicyclic AMPA analogues appears to be of importance for the potency and efficacy of these compounds.
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，2）是兴奋性氨基酸受体（RS）-2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸（AMPA）亚型的功能性部分激动剂，这表明（S）-APPA是AMPA受体的完全激动剂，而（R）-APPA是AMPA受体的竞争性拮抗剂。我们现已合成并对（RS）-2-氨基-3-[3-羟基-5-（2-氟苯基）异恶唑-4-基]丙酸（2-F-APPA，5a）、3-F-APPA（5b）、4-F-APPA（5c）、（S）-4-F-APPA（6）、（R）-4-F-APPA（7）以及分别为完全和部分饱和的APPA（2）类似物，即（RS）-2-氨基-3-（3-羟基-5-环己基异恶唑-4-基）丙酸（5d）和含有1-环己烯基环的化合物5e进行了药理学表征。基于对6、7以及（S）-和（R）-APPA的比较圆二色性研究确定了6和7的绝对立体化学。4-F-APPA（5c）、（S）-4-F-APPA（6）、5d和5e被证明可选择性抑制[3H]AMPA结合并激活AMPA受体。虽然（S）-4-F-APPA（6）表现出完全的AMPA受体激动作用，但（R）-4-F-APPA（7）是AMPA受体拮抗剂。将（S）-和（R）-4-F-APPA共同给予大鼠皮质楔形制剂可产生功能性部分AMPA受体激动作用。半经验计算表明，在一系列非稠合双环AMPA类似物中连接两个环的键的扭转角大小似乎对这些化合物的效力和功效很重要。
