Vestergaard Henrik T, Vogensen Stine B, Madsen Ulf, Ebert Bjarke
Department of Pharmacology, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen Ø, Denmark.
Eur J Pharmacol. 2004 Mar 19;488(1-3):101-9. doi: 10.1016/j.ejphar.2004.02.024.
Quisqualic acid induces sensitisation of neurones to depolarisation by analogues of 2-amino-4-phosphonobutyric acid (AP4), phenylglycine, and homoibotenic acid (HIBO). Thus, after administration of quisqualate these analogues become active at concentrations at which they are otherwise inactive. The mechanisms behind quisqualate-induced sensitisation are poorly understood and have not previously been quantified properly. In this study, we have tested the activity of a number of 4-alkyl- and 4-aryl-substituted analogues of HIBO as regards quisqualate-sensitisation, and present a method for quantifying the sensitisation induced by quisqualate at cortical neurones. These analogues are generally more potent and selective than (S)-AP4 or its homologue (S)-AP5 following quisqualate-sensitisation. Furthermore, we found a statistically significant correlation between the ligands' ability to inhibit CaCl(2)-dependent (S)-[(3)H]glutamate uptake into rat cortical synaptosomes, and their potency following quisqualate-induced depolarisation. This demonstrates the involvement of a transport system in the mechanism underlying the quisqualate-effect.
喹啉酸可使神经元对2-氨基-4-膦酰丁酸（AP4）、苯甘氨酸和高鹅膏蕈氨酸（HIBO）类似物诱导的去极化产生敏感化。因此，给予喹啉酸盐后，这些类似物在原本无活性的浓度下变得具有活性。喹啉酸盐诱导敏感化背后的机制尚不清楚，此前也未得到恰当的量化。在本研究中，我们测试了多种HIBO的4-烷基和4-芳基取代类似物对喹啉酸盐敏感化的活性，并提出了一种量化喹啉酸盐在皮质神经元中诱导敏感化的方法。在喹啉酸盐敏感化后，这些类似物通常比（S）-AP4或其同系物（S）-AP5更有效且更具选择性。此外，我们发现配体抑制CaCl₂依赖性（S）-[³H]谷氨酸摄取到大鼠皮质突触体的能力与其在喹啉酸盐诱导的去极化后的效力之间存在统计学上的显著相关性。这表明转运系统参与了喹啉酸盐效应背后的机制。
