1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride
• 英文别名: 1,4,5,6-tetrahydropyrimidine-5-carboxylic acid;hydrochloride
• 化学式: C₅H₈N₂O₂*ClH
• 分子量: 164.592
• InChiKey: TXTRXEIKYAFUIX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.26
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  61.7
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride 在 草酰氯 作用下， 以 苯 为溶剂， 反应 2.5h， 生成 1,4,5,6-四氢-5-嘧啶羰基氯化物
  参考文献：
  名称：

  Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists

  摘要：

  Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.

  DOI：

  10.1021/jm960467d
• 作为产物：
  描述：

  5-嘧啶羧酸盐酸盐 在 5% rhodium on carbon 、 氢气 作用下， 以 水 为溶剂， 以49%的产率得到1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABAA receptor agonists

  摘要：

  A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABA(A)R binding affinities to native GABA(A) receptors (K(i) 1.1-24 μM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K(i) 0.044 μM) and equipotency as an agonist to GABA itself as well as the standard GABA(A) agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a α1β2γ2 GABA(A) receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABA(A)R agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABA(A)R area.

  DOI：

  10.1016/j.ejmech.2014.07.039

文献信息

• Muscarinic agonists
  申请人：The University of Toledo

  公开号：US05175166A1

  公开（公告）日：1992-12-29

  Substituted 1,4,5,6 -tetrahydropyrimidine compositions, substituted 1,2,3,6-tetrahydropyrimidine compositions and substituted 3,4,5,6-tetrahydropyridine compositions are disclosed. They are useful for stimulating muscarinic receptors including, for example, treating the symptoms of cognitive disorders, especially impared memory, which are associated with decreased acetylcholine synthesis and cholinergic cell degeneration.

  揭示了替代的1,4,5,6-四氢嘧啶组合物、替代的1,2,3,6-四氢嘧啶组合物和替代的3,4,5,6-四氢吡啶组合物。它们可用于刺激肌氨酸受体，例如治疗认知障碍的症状，特别是与乙酰胆碱合成减少和胆碱能细胞退化相关的记忆障碍。
• Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists
  作者：Babatunde Ojo、Philip G. Dunbar、Graham J. Durant、Peter I. Nagy、James J. Huzl、Sumudra Periyasamy、Dan O. Ngur、Afif A. El-Assadi、Wayne P. Hoss、William S. Messer

  DOI：10.1016/0968-0896(96)00152-6

  日期：1996.10

  development of selective, efficacious, and centrally active m1 muscarinic agonists for the treatment of Alzheimer's disease, a series of amide and hydrazide amidine derivatives (2a-e and 3b-d) was synthesized and examined for muscarinic agonist activity. Preliminary biochemical studies indicated that 2b, 2d, and 3d bound to muscarinic receptors in rat brain and stimulated phosphoinositide (PI) metabolism

  作为旨在开发选择性，有效和中枢活性的m1毒蕈碱激动剂以治疗阿尔茨海默氏病的持续努力的一部分，合成了一系列酰胺和酰肼am衍生物（2a-e和3b-d）并检查了毒蕈碱激动剂活性。初步的生化研究表明，2b，2d和3d与大鼠脑中的毒蕈碱受体结合，并刺激大鼠大脑皮层中的磷酸肌醇（PI）代谢。化合物2b和2d对在培养的A9L细胞中表达的m1毒蕈碱受体也非常有效。分子模型研究表明，与酯和酰胺衍生物的m1受体相互作用的方式略有不同。同样，具有Thr残基的氢键形成对于m1毒蕈碱激动剂的效力可能很重要。
• MUSCARINIC AGONISTS
  申请人：THE UNIVERSITY OF TOLEDO

  公开号：EP0630244A1

  公开（公告）日：1994-12-28
• EP0630244A4
  申请人：——

  公开号：EP0630244A4

  公开（公告）日：1994-04-07
• US5175166A
  申请人：——

  公开号：US5175166A

  公开（公告）日：1992-12-29