Janssen Research and Development, Beerse, Belgium.
J Pharmacol Exp Ther. 2013 Sep;346(3):514-27. doi: 10.1124/jpet.113.204990. Epub 2013 Jun 13.
Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (JNJ-40068782) and its radioligand [(3)H]JNJ-40068782. In guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, JNJ-40068782 produced a leftward and upward shift in the glutamate concentration-effect curve at human recombinant mGlu2 receptors. The EC50 of JNJ-40068782 for potentiation of an EC20-equivalent concentration of glutamate was 143 nM. Although JNJ-40068782 did not affect binding of the orthosteric antagonist [(3)H]2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495), it did potentiate the binding of the agonist (3)H-2-(2',3'-dicarboxylcyclopropyl)glycine (DCG-IV), demonstrating that it can allosterically affect binding at the agonist recognition site. The binding of [(3)H]JNJ-40068782 to human recombinant mGlu2 receptors in Chinese hamster ovary cells and rat brain receptors was saturable with a KD of ∼10 nM. In rat brain, the anatomic distribution of [(3)H]JNJ-40068782 was consistent with mGlu2 expression previously described and was most abundant in cortex and hippocampus. The ability of structurally unrelated PAMs to displace [(3)H]JNJ-40068782 suggests that PAMs may bind to common determinants within the same site. It is noteworthy that agonists also increased the binding affinity of [(3)H]JNJ-40068782. JNJ-40068782 influenced rat sleep-wake organization by decreasing rapid eye movement sleep with a lowest active dose of 3 mg/kg PO. In mice, JNJ-40068782 reversed phencyclidine-induced hyperlocomotion with an ED50 of 5.7 mg/kg s.c. Collectively, the present data demonstrate that JNJ-40068782 has utility in investigating the potential of mGlu2 modulation for the treatment of diseases characterized by disturbed glutamatergic signaling and highlight the value of [(3)H]JNJ-40068782 in exploring allosteric binding.
代谢型谷氨酸受体 2（mGlu2）的调制被认为是治疗精神分裂症等中枢神经系统疾病的有希望的靶点。在这里，我们描述了新型 mGlu2 受体正变构调节剂（PAM）3-氰基-1-环丙基甲基-4-（4-苯基-哌啶-1-基）-吡啶-2（1H）-酮（JNJ-40068782）及其放射性配体[3H]JNJ-40068782 的药理学特性。在鸟苷 5'-O-（3-[(35)S]硫代）三磷酸结合中，JNJ-40068782 使人类重组 mGlu2 受体上的谷氨酸浓度效应曲线向左和向上移位。JNJ-40068782 增强 EC20 等效浓度谷氨酸的 EC50 为 143 nM。尽管 JNJ-40068782 不影响正位拮抗剂[3H]2S-2-氨基-2-（1S，2S-2-羧基环丙基-1-基）-3-（黄嘌呤-9-基）丙酸（LY-341495）的结合，但它确实增强了激动剂[3H]（2S，2'R，3'R）-2-（2'，3'-二羧基环丙基）甘氨酸（DCG-IV）的结合，表明它可以变构影响激动剂识别位点的结合。[3H]JNJ-40068782 在中华仓鼠卵巢细胞和大鼠脑受体中的人重组 mGlu2 受体上的结合是饱和的，KD约为 10 nM。在大鼠脑中，[3H]JNJ-40068782 的分布与先前描述的 mGlu2 表达一致，在皮质和海马体中最为丰富。结构上不相关的 PAMs 置换[3H]JNJ-40068782 的能力表明 PAMs 可能结合到同一部位的共同决定因素上。值得注意的是，激动剂也增加了[3H]JNJ-40068782 的结合亲和力。JNJ-40068782 通过降低快速眼动睡眠（REM）睡眠来影响大鼠的睡眠-觉醒组织，最低有效剂量为 3 毫克/千克 PO。在小鼠中，JNJ-40068782 以 5.7 毫克/千克 SC 的 ED50 逆转了苯环利定引起的过度运动。总的来说，目前的数据表明，JNJ-40068782 可用于研究 mGlu2 调节治疗以谷氨酸信号传递紊乱为特征的疾病的潜力，并强调了[3H]JNJ-40068782 在探索变构结合中的价值。
