JNJ 16259685 is a potent and selective mGlu1 receptor antagonist with an IC50 value of 19nM[1]. JNJ 16259685 acts on the mGlu1 receptor in a non-competitive manner and completely inhibits the increase in intracellular Ca2+ concentration of cells induced by glutamate, with an IC50 value of 3.24nM and excellent brain permeability [2]. JNJ 16259685 has been widely used to block the mGluR1-dependent currents in dopamine neurons[3].
In vitro, JNJ 16259685 treatment (10μM) for 24h can eliminate the increase in intracellular Ca2+ caused by glutamate and prevent glutamate-induced cell apoptosis in rat neuron cells[4].
In vivo, JNJ 16259685 treatment via a single intraperitoneal injection at a dose of 8mg/kg of JNJ 16259685 for 30 minutes inhibited the isolation-induced aggressive behavior in male mice[5]. In rats with subarachnoid hemorrhage (SAH), intraperitoneal injection of JNJ 16259685 (10mg/kg) at 2 hours, 24 hours and 48 hours after the injury can alleviate blood-brain barrier damage and brain edema, restore the level of vascular active polypeptide (VASP) and inhibit the expression of AQP4[6]. A single subcutaneous injection of 1mg/kg dose of JNJ 16259685 for 30min impaired the movement and coordination abilities of mice, and inhibited the exploratory behavior[7].
References:
[1] Fukunaga I, Yeo C H, Batchelor A M. Potent and specific action of the mGlu1 antagonists YM‐298198 and JNJ16259685 on synaptic transmission in rat cerebellar slices[J]. British journal of pharmacology, 2007, 151(6): 870-876.
[2] Steckler T, Lavreysen H, Oliveira A M, et al. Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test[J]. Psychopharmacology, 2005, 179(1): 198-206.
[3] Kramer P F, Williams J T. Cocaine decreases metabotropic glutamate receptor mGluR1 currents in dopamine neurons by activating mGluR5[J]. Neuropsychopharmacology, 2015, 40(10): 2418-2424.
[4] Zhang Z, Liu J, Fan C, et al. The GluN1/GluN2B NMDA receptor and metabotropic glutamate receptor 1 negative allosteric modulator has enhanced neuroprotection in a rat subarachnoid hemorrhage model[J]. Experimental neurology, 2018, 301: 13-25.
[5] Navarro J F, De Castro V, Martín-López M. JNJ16259685, a selective mGlu1 antagonist, suppresses isolation-induced aggression in male mice[J]. European Journal of Pharmacology, 2008, 586(1-3): 217-220.
[6] Zhang C, Jiang M, Wang W, et al. Selective mGluR1 negative allosteric modulator reduces blood–brain barrier permeability and cerebral edema after experimental subarachnoid hemorrhage[J]. Translational stroke research, 2020, 11(4): 799-811.
[7] Hodgson R A, Hyde L A, Guthrie D H, et al. Characterization of the selective mGluR1 antagonist, JNJ16259685, in rodent models of movement and coordination[J]. Pharmacology Biochemistry and Behavior, 2011, 98(2): 181-187.
JNJ 16259685是一种强效且选择性的mGlu1受体拮抗剂，IC50值为19nM[1]。JNJ 16259685以非竞争性方式作用于mGlu1受体，能完全抑制谷氨酸诱导的细胞内Ca2+浓度的升高，IC50值为3.24nM，并具有优异的脑通透性[2]。JNJ 16259685已被广泛用于阻断多巴胺神经元中mGluR1依赖性电流[3]。
在体外，使用10μM的JNJ 16259685 处理大鼠神经元细胞24小时，可消除谷氨酸引起的细胞内Ca2+增加，并防止谷氨酸诱导的细胞凋亡[4]。
在体内，单次腹腔注射8mg/kg剂量的 JNJ 16259685，持续 30 分钟，可抑制雄性小鼠由隔离诱发的攻击行为[5]。在蛛网膜下腔出血（SAH）大鼠中，于损伤后2小时、24小时和48小时腹腔注射JNJ 16259685（10mg/kg），可减轻血脑屏障损伤和脑水肿，恢复vascular active polypeptide (VASP)水平，并抑制AQP4的表达[6]。单次皮下注射1mg/kg剂量的JNJ 16259685，持续30分钟，会损害小鼠的运动和协调能力，并抑制小鼠探索行为[7]。