Weiss Brianne, Alt Andrew, Ogden Ann Marie, Gates Mary, Dieckman Donna K, Clemens-Smith Amy, Ho Ken H, Jarvie Keith, Rizkalla Geihan, Wright Rebecca A, Calligaro David O, Schoepp Darryle, Mattiuz Edward L, Stratford Robert E, Johnson Bryan, Salhoff Craig, Katofiasc Mary, Phebus Lee A, Schenck Kathryn, Cohen Marlene, Filla Sandra A, Ornstein Paul L, Johnson Kirk W, Bleakman David
Eli Lilly and Company, Neuroscience Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
J Pharmacol Exp Ther. 2006 Aug;318(2):772-81. doi: 10.1124/jpet.106.101428. Epub 2006 May 11.
The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU(K5) in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU(K5)-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLU(K5) antagonist described to date. Comparisons were made to the competitive GLU(K5)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU(K5) receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 microM)-induced currents with an IC50 value of 0.045 +/- 0.011 microM. In HEK293 cells transfected with GLU(K5), GLU(K2)/GLU(K5), or GLU(K5)/GLU(K6) receptors, LY466195 produced IC50 values of 0.08 +/- 0.02, 0.34 +/- 0.17, and 0.07 +/- 0.02 microM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID100 value of 100 microg/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 microg/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 microg/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.
兴奋性神经递质谷氨酸已被认为与偏头痛和持续性疼痛有关。在背根神经节、背角和三叉神经节中发现了红藻氨酸受体GLU(K5)，这使其成为这些适应症的一个感兴趣的靶点。我们研究了竞争性GLU(K5)选择性红藻氨酸受体拮抗剂LY466195 [（3S,4aR,6S,8aR）-6-[[(2S)-2-羧基-4,4-二氟-1-吡咯烷基]甲基]十氢异喹啉-3-羧酸]的体外和体内药理学特性，它是迄今为止描述的最有效的GLU(K5)拮抗剂。将其与竞争性GLU(K5)/α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂LY293558 [（3S,4aR,6R,8aR）-6-[2-(1(2)H-四唑-5-基)乙基]十氢异喹啉-3-羧酸]、其他十氢异喹啉GLU(K5)受体拮抗剂以及非竞争性AMPA受体拮抗剂LY300168 [1-(4-氨基苯基)-4-甲基-7,8-亚甲基二氧基-5H-2,3-苯并二氮杂卓]进行了比较。当在大鼠背根神经节神经元中进行电生理特性分析时，LY466195拮抗红藻氨酸（30 microM）诱导的电流，IC50值为0.045±0.011 microM。在转染了GLU(K5)、GLU(K2)/GLU(K5)或GLU(K5)/GLU(K6)受体的HEK293细胞中，LY466195产生的IC50值分别为0.08±0.02、0.34±0.17和0.07±0.02 microM。LY466195在偏头痛的硬脑膜血浆蛋白外渗（PPE）模型中有效，静脉注射ID100值为100 microg/kg。LY466195在c-fos偏头痛模型中也有效，静脉注射剂量为1 microg/kg时，在电刺激三叉神经节后，可显著减少大鼠尾状核中Fos阳性细胞的数量。此外，LY466195在体外兔隐静脉中未表现出收缩活性。LY466195的二乙酯前药在分别以10和100 microg/kg的口服剂量给药后，在相同的PPE和c-fos模型中也有效，而在口服剂量高达100 mg/kg时没有N-甲基-D-天冬氨酸拮抗剂样的行为效应。
