Madsen U, Bräuner-Osborne H, Frydenvang K, Hvene L, Johansen T N, Nielsen B, Sánchez C, Stensbøl T B, Bischoff F, Krogsgaard-Larsen P
Centre for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
J Med Chem. 2001 Mar 29;44(7):1051-9. doi: 10.1021/jm000441t.
Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K(b) = 30 microM at mGlu(1) and K(b) = 61 microM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K(b) = 160 microM) showing very weak antagonist effect at mGlu(5) (K(b) = 990 microM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC(50) = 395 microM, K(b) = 86 and 90 microM, respectively). Compound 9, administered icv, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.
以鹅膏蕈氨酸（2）为先导化合物，已开发出用于（S）-谷氨酸（Glu，1）受体的两个系列的3-异恶唑醇氨基酸配体。（RS）-2-氨基-3-（3-羟基-5-甲基-4-异恶唑基）丙酸[AMPA，（RS）-3]的类似物选择性地与离子型谷氨酸受体（iGluRs）相互作用，而迄今为止已知的（RS）-2-氨基-3-（3-羟基-5-异恶唑基）丙酸[HIBO，（RS）-4]的少数类似物通常与离子型谷氨酸受体以及代谢型谷氨酸受体（mGluRs）相互作用。我们在此报告了一系列HIBO的4-取代类似物的合成及药理学研究。已证明己基类似物9是I组mGluRs的拮抗剂。9的作用仅存在于（S）-9中（在mGlu（1）处Kb = 30 microM，在mGlu（5）处Kb = 61 microM）。9的低级同系物化合物8在mGluRs上表现出类似的作用，但8也是离子型谷氨酸受体AMPA亚型的弱激动剂。与9一样，高级同系物化合物10不与离子型谷氨酸受体相互作用，但10选择性拮抗mGlu（1）（Kb = 160 microM），在mGlu（5）处显示出非常弱的拮抗作用（Kb = 990 microM）。苯基类似物11被证明是一种AMPA激动剂以及mGlu（1）和mGlu（5）的拮抗剂，并且这些作用被证明源自（S）-11（EC50 = 395 microM，Kb分别为86和90 microM）。已证明经脑室内（icv）而非皮下（sc）给药的化合物9可保护小鼠免受N-甲基-D-天冬氨酸（NMDA）诱导的惊厥。使用手性高效液相色谱法拆分了化合物9和11，对映体的构型归属基于X射线晶体学分析。
