3-氨基-N-[（4-甲氧基苯基）甲基]-4,6-二甲基噻吩并[2,3-b]吡啶-2-羧酰胺 | 409351-28-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并吡啶类
• 中文名称: 3-氨基-N-[（4-甲氧基苯基）甲基]-4,6-二甲基噻吩并[2,3-b]吡啶-2-羧酰胺
• 中文别名: 3-氨基-N-[(4-甲氧基苯基)甲基]-4,6-二甲基噻吩并[2,3-B]吡啶-2-甲酰胺
• 英文名称: VU0152100
• 英文别名: 3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide；VU152100；3-amino-N-[(4-methoxyphenyl)methyl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide
• CAS: 409351-28-6
• 化学式: C₁₈H₁₉N₃O₂S
• 分子量: 341.434
• InChiKey: MDNWGCQSCGNTKH-UHFFFAOYSA-N

物化性质

• 密度：
  1.282
• 溶解度：
  二甲基亚砜：>50mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 危险类别：
  6.1
• 危险性防范说明：
  P301+P310,P305+P351+P338
• 危险品运输编号：
  2811
• 危险性描述：
  H301,H319
• 包装等级：
  III

制备方法与用途

生物活性方面，VU0152100 是 M4mAChR 的变构增强剂，其 EC50 值为 380 nM。

反应信息

• 作为反应物：
  描述：

  3-氨基-N-[（4-甲氧基苯基）甲基]-4,6-二甲基噻吩并[2,3-b]吡啶-2-羧酰胺 、 苯甲酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 以54%的产率得到3-benzamido-N-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide
  参考文献：
  名称：

  Simultaneous activation of muscarinic and GABAB receptors as a bidirectional target for novel antipsychotics

  摘要：

  Recent preclinical studies point to muscarinic and GABA(B) receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABA(B) receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABA(B) receptor (GS39783), muscarinic M-4 (VU0152100) and M-5 (VU0238429) receptor, and partial allosteric agonist of M-1 receptor (VU0357017).DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. lialoperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs.All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOl-induced 5EPSC5. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions.Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.

  DOI：

  10.1016/j.bbr.2018.09.019

文献信息

• TREATMENT OF LEVODOPA-INDUCED DYSKINESIAS
  申请人：NORTHWESTERN UNIVERSITY

  公开号：US20160354330A1

  公开（公告）日：2016-12-08

  Provided herein are compositions and methods for the treatment and prevention of levodopa-induced dyskinesias (LID). In particular, M4 muscarinic receptor (M4R) positive allosteric modulators (PAMs) are administered to reduce dyskinetic behavior.
• Simultaneous activation of muscarinic and GABAB receptors as a bidirectional target for novel antipsychotics
  作者：Paulina Cieślik、Monika Woźniak、Krzysztof Tokarski、Magdalena Kusek、Andrzej Pilc、Agata Płoska、Adrianna Radulska、Iwona Pelikant-Małecka、Beata Żołnowska、Jarosław Sławiński、Leszek Kalinowski、Joanna M Wierońska

  DOI：10.1016/j.bbr.2018.09.019

  日期：2019.2

  Recent preclinical studies point to muscarinic and GABA(B) receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABA(B) receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABA(B) receptor (GS39783), muscarinic M-4 (VU0152100) and M-5 (VU0238429) receptor, and partial allosteric agonist of M-1 receptor (VU0357017).DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. lialoperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs.All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOl-induced 5EPSC5. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions.Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.