3-cyclopropyl-5-(1-methyl-1,2,5,6-tetrahydropyridin3-yl)-1,2,4-oxadiazole oxalate | 114904-31-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-cyclopropyl-5-(1-methyl-1,2,5,6-tetrahydropyridin3-yl)-1,2,4-oxadiazole oxalate
• 英文别名: 3-cyclopropyl-5-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,4-oxadiazole
• CAS: 114904-31-3
• 化学式: C₁₁H₁₅N₃O
• 分子量: 205.26
• InChiKey: VVEWBCPBISEDBT-UHFFFAOYSA-N

物化性质

• 沸点：
  345.9±52.0 °C(predicted)
• 密度：
  1.205±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  42.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  槟榔碱 、 N-hydroxycyclopropanecarboximidamide 生成 3-cyclopropyl-5-(1-methyl-1,2,5,6-tetrahydropyridin3-yl)-1,2,4-oxadiazole oxalate
  参考文献：
  名称：

  SAUERBERG, PER;KINDTLER, JENS W.;NIELSEN, LONE;SHEARDOWN, MALCOLM J.;HONO+, J. MED. CHEM., 34,(1991) N, C. 687-692

  摘要：

  DOI：

文献信息

• Novel Antimuscarinic Antidepressant-like Compounds with Reduced Effects on Cognition
  作者：Chad R. Johnson、Brian D. Kangas、Emily M. Jutkiewicz、Gail Winger、Jack Bergman、Andrew Coop、James H. Woods

  DOI：10.1124/jpet.120.000337

  日期：2021.6

  The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage of the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggravate cognitive deficits that occur with depression itself. Thus, the identification of antimuscarinic drugs that are free of such detrimental effects may provide an important avenue for the development of novel therapeutics for the management of depression. The present data in rats indicate that a historical muscarinic antagonist, L-687,306, and a muscarinic antagonist of our own design, CJ2100, were as or more effective than scopolamine in antagonizing both the bradycardic effects of the muscarinic agonist arecoline in cardiovascular studies and its discriminative stimulus and rate-decreasing effects in behavioral studies. Additionally, both novel muscarinic antagonists were as effective as scopolamine in decreasing immobility in the forced swim test, a preclinical indicator of potential antidepressant activity. However, at equieffective or even larger doses, they were considerably less disruptive than scopolamine in assays of cognition-related behavior. All three drugs displayed high specificity for the mAChRs with few off-target binding sites, and CJ2100 showed modest affinity across the mAChRs when compared with L-687,306 and scopolamine. These data emphasize the dissimilar pharmacological profiles that are evident across antimuscarinic compounds and the potential utility of novel antagonists for the improved treatment of depression. SIGNIFICANCE STATEMENT Some clinical studies with the muscarinic antagonist scopolamine document its ability to produce antidepressant effects in patients with mood disorders; however, scopolamine also has well known adverse effects on both autonomic and centrally mediated physiological functions that limit its therapeutic use. This study characterizes the cardiovascular and discriminative stimulus effects of two novel muscarinic antagonists, L-687,306 and CJ2100, that produce antidepressant-like effects in a rodent model (forced swim test) without affecting touchscreen-based cognitive performance (titrating psychomotor vigilance and delayed matching-to-position).

  胆碱能神经系统与情绪障碍密切相关，这在临床研究中表现为阿托品（一种强效的毒蕈碱拮抗剂）快速起效的抗抑郁作用。使用阿托品治疗抑郁症的一个显著缺点是对认知的负面影响，尤其是这些影响可能加剧抑郁症本身所导致的认知缺陷。因此，识别不具有这些有害影响的抗毒蕈碱药物可能为开发新型治疗抑郁症的药物提供重要途径。目前在大鼠中的数据表明，历史上已知的毒蕈碱拮抗剂L-687,306，以及我们自行设计的毒蕈碱拮抗剂CJ2100，在抵消心血管研究中毒蕈碱受体激动剂阿瑞可林的心动过缓效应以及在行为研究中的分辨刺激和降低速率效果方面，效果与阿托品相当或更为显著。此外，这两种新型毒蕈碱拮抗剂在强迫游泳试验中减少无动性的效果与阿托品相当，该试验是潜在抗抑郁活性的前临床指示。然而，在等效或更高剂量下，它们在认知相关行为的测量中对行为的干扰程度明显低于阿托品。这三种药物对mAChRs显示出高度特异性，几乎没有偏离靶点的结合位点，并且与L-687,306和阿托品相比，CJ2100在mAChRs上显示出适度的亲和力。这些数据强调了不同的抗毒蕈碱化合物之间明显不同的药理特征，以及新型拮抗剂在改善抑郁症治疗中的潜在用途。 重要声明：一些与毒蕈碱拮抗剂阿托品相关的临床研究记录了其在情绪障碍患者中产生抗抑郁效果的能力；然而，阿托品对自主神经及中枢介导的生理功能的负面影响是众所周知的，这限制了其治疗用途。本研究描述了两种新型毒蕈碱拮抗剂L-687,306和CJ2100的心血管和分辨刺激效果，这两者在啮齿动物模型（强迫游泳试验）中产生类似抗抑郁的效果，同时没有影响基于触摸屏的认知表现（逐级心理运动警觉性和延迟匹配位置）。
• Piperidine compounds and their preparation and use
  申请人：NOVO NORDISK A/S

  公开号：EP0259621A2

  公开（公告）日：1988-03-16

  New piperidine compounds having the formula wherein at least one of R³, R⁴, and R⁵ are and the other independently are H or C1-6-alkyl, wherein Rʹ is H, C1-8-alkyl, phenyl, thienyl, cyclopropyl, or C1-3-alkoxymethyl; and R¹ and R⁶ independently are H or C1-6-alkyl and a salt thereof with a pharmaceutically-acceptable acid. The new compounds are useful in improving the cognitive functions of the forebrain and hippocampus of mammals, and are useful in the treatment of Alzheimer's disease.

  具有以下式子的新哌啶化合物 式中 R³、R⁴ 和 R⁵ 中至少有一个是 和 R⁵ 中至少有一个是 H 或 C1-6-烷基、 其中 Rʹ 是 H、C1-8-烷基、苯基、噻吩基、环丙基或 C1-3- 烷氧基甲基；以及 R¹和 R⁶各自为 H 或 C1-6- 烷基 及其与药学上可接受的酸的盐。 新化合物有助于改善哺乳动物前脑和海马的认知功能，并可用于治疗阿尔茨海默氏症。
• Muscarinic cholinergic agonists and antagonists of the 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridine type. Synthesis and structure-activity relationships
  作者：Per Sauerberg、Jens W. Kindtler、Lone Nielsen、Malcolm J. Sheardown、Tage Honore

  DOI：10.1021/jm00106a033

  日期：1991.2

  A series of 3-(3-alkyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyridines (2a-q) were synthesized and tested for central muscarinic cholinergic receptor binding affinity by using [H-3]oxotremorine-M and [H-3]QNB as ligands and in a functional assay using guinea pig ileum. The analogues with unbranched C1-8-alkyl substituents (2a-g) were agonist, whereas the compounds with branched or cyclic substituents (2h-m) were antagonists. The alkyl ether analogues (2o-q) were also agonists but had lower receptor binding affinity than the corresponding alkyl analogues. The 3-(5-alkyl-1,2,4-oxadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine analogues had only very low affinity for the central muscarinic receptors and were weak antagonists in the ileum assay. A few 3-(3-butyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-1-methylpyridines substituted with methyl or hydrogen in the 1-, 5-, or 6-position were synthesized and tested. N-Desmethyl analogue 7 was a potent muscarinic agonist, whereas N-desmethyl-5-methyl analogue 11 and N-methyl-6-methyl analogue 13 both were antagonists with lower muscarinic receptor affinity. The 3-(3-butyl-1,2,4-oxadiazol-5-yl)quinuclidine (17) and tropane (15) analogues were both very potent antagonists with high affinity for central muscarinic receptors. The ratio [IC50(QNB)/IC50(Oxo-M)] x 0.162 proved to be a good indicator of the efficacy of the compounds in the guinea pig ileum assay.
• METHODS OF USING MUSCARINIC ANTAGONISTS IN THE TREATMENT OF DEPRESSION
  申请人：COOP Andrew

  公开号：US20220152005A1

  公开（公告）日：2022-05-19

  Muscarinic antagonist are provided that are used in the treatment of depression in a subject, such as humans. The muscarinic antagonist of the invention can relieve depression without effecting cognitive functions in the treated subject.