Schoepp D D, Johnson B G, Smith E C, McQuaid L A
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Mol Pharmacol. 1990 Aug;38(2):222-8.
DL-2-Amino-3-phosphonopropionic acid, a phosphonate-substituted derivative of aspartic acid, has been shown to be an inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis in rat brain slices. In this study, the enantiomers of 2-amino-3-phosphonopropionic acid were synthesized and used to further characterize the stereoselectivity and mechanism of interaction of this compound for inhibiting phosphoinositide-coupled (metabotropic) excitatory amino acid receptors. L-2-Amino-3-phosphonopropionic acid was 3-5 times more potent than D-2-amino-3-phosphonopropionic acid as an inhibitor of ibotenate-stimulated [3H]inositol monophosphate formation in slices of the rat hippocampus or quisqualate-stimulated [3H]inositol monophosphate formation in neonatal rat cerebral cortical slices. Carbachol-stimulated phosphoinositide hydrolysis was not inhibited by L-2-amino-3-phosphonopropionic acid, and L-2-amino-3-phosphonopropionic acid had no appreciable affinity for ionotropic excitatory amino acid receptors at concentrations required to inhibit metabotropic excitatory amino acid responses. The inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid on phosphoinositide hydrolysis were not competitive, because they could not be surmounted by increasing concentrations of ibotenate or quisqualate. L-2-Amino-3-phosphonopropionic acid inhibition also could not be prevented by washing the tissue before incubation with ibotenate. Thus, L-2-amino-3-phosphonopropionic acid is a stereoselective inhibitor of metabotropic excitatory amino acid receptors with little affinity for ionotropic receptors. However, the inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid were not readily reversed, and the site at which they act to inhibit metabotropic excitatory amino acid receptors remains to be determined.
DL-2-氨基-3-膦酰丙酸是天冬氨酸的一种膦酸酯取代衍生物，已被证明是大鼠脑片中兴奋性氨基酸刺激的磷酸肌醇水解的抑制剂。在本研究中，合成了2-氨基-3-膦酰丙酸的对映体，并用于进一步表征该化合物抑制磷酸肌醇偶联（促代谢型）兴奋性氨基酸受体的立体选择性和相互作用机制。作为大鼠海马切片中鹅膏蕈氨酸刺激的[3H]肌醇单磷酸形成或新生大鼠大脑皮层切片中喹啉酸刺激的[3H]肌醇单磷酸形成的抑制剂，L-2-氨基-3-膦酰丙酸的效力比D-2-氨基-3-膦酰丙酸强3至5倍。L-2-氨基-3-膦酰丙酸不抑制卡巴胆碱刺激的磷酸肌醇水解，并且在抑制促代谢型兴奋性氨基酸反应所需的浓度下，L-2-氨基-3-膦酰丙酸对离子型兴奋性氨基酸受体没有明显亲和力。L-2-氨基-3-膦酰丙酸或L-2-氨基-4-膦酰丁酸对磷酸肌醇水解的抑制作用不具有竞争性，因为增加鹅膏蕈氨酸或喹啉酸的浓度不能克服这种抑制作用。在用鹅膏蕈氨酸孵育之前洗涤组织也不能阻止L-2-氨基-3-膦酰丙酸的抑制作用。因此，L-2-氨基-3-膦酰丙酸是促代谢型兴奋性氨基酸受体的立体选择性抑制剂，对离子型受体几乎没有亲和力。然而，L-2-氨基-3-膦酰丙酸或L-2-氨基-4-膦酰丁酸的抑制作用不易逆转，它们抑制促代谢型兴奋性氨基酸受体的作用位点仍有待确定。
