Desai M A, Burnett J P, Ornstein P L, Schoepp D D
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
J Pharmacol Exp Ther. 1995 Jan;272(1):38-43.
Activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of ionotropic glutamate receptors by certain agonists, including AMPA and glutamate, has been shown to result in a rapid desensitization of the receptor. This desensitization is profoundly inhibited by the benzothiadiazide diuretic, cyclothiazide. We previously reported that cyclothiazide potentiates AMPA-induced [3H]norepinephrine ([3H]NE) release from rat hippocampal slices. We used this system to investigate the possible interaction of cyclothiazide with various AMPA receptor antagonists, including the competitive antagonist LY293558 and the 2,3-benzodiazepine noncompetitive antagonist GYKI 53655. Cyclothiazide significantly potentiated both AMPA- and KA-induced [3H]NE release from slices of the rat hippocampus. LY293558 and GYKI 53655 inhibited the potentiated and nonpotentiated AMPA- and KA-induced [3H]NE release in a concentration-dependent manner. The IC50 values for inhibition of AMPA- or KA-induced [3H]NE release by either antagonist were not affected by the presence of cyclothiazide. Thus, cyclothiazide seems to interact at a site on the AMPA receptor complex which differs from either the glutamate recognition site or the 2,3-benzodiazepine allosteric site.
包括AMPA和谷氨酸在内的某些激动剂对离子型谷氨酸受体的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）亚型的激活已被证明会导致该受体的快速脱敏。这种脱敏受到苯并噻二嗪类利尿剂环噻嗪的显著抑制。我们之前报道过环噻嗪可增强AMPA诱导的大鼠海马切片中[3H]去甲肾上腺素（[3H]NE）的释放。我们利用这个系统来研究环噻嗪与各种AMPA受体拮抗剂之间可能的相互作用，包括竞争性拮抗剂LY293558和2,3-苯并二氮杂䓬非竞争性拮抗剂GYKI 53655。环噻嗪显著增强了AMPA和KA诱导的大鼠海马切片中[3H]NE的释放。LY293558和GYKI 53655以浓度依赖的方式抑制了增强的和未增强的AMPA和KA诱导的[3H]NE释放。两种拮抗剂抑制AMPA或KA诱导的[3H]NE释放的IC50值不受环噻嗪存在的影响。因此，环噻嗪似乎在AMPA受体复合物上的一个位点相互作用，该位点不同于谷氨酸识别位点或2,3-苯并二氮杂䓬变构位点。
