8-ethoxycarbonyl-3β-(4-chlorophenyl)-3α-hydroxy-8-azabicyclo[3.2.1]octane | 83393-32-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: 8-ethoxycarbonyl-3β-(4-chlorophenyl)-3α-hydroxy-8-azabicyclo[3.2.1]octane
• 英文别名: ethyl 3-(4-chlorophenyl)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate；endo-8-ethoxycarbonyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol
• CAS: 83393-32-2
• 化学式: C₁₆H₂₀ClNO₃
• 分子量: 309.793
• InChiKey: CDBBYROYBQMWGJ-FOLVSLTJSA-N

物化性质

• 沸点：
  442.7±45.0 °C(Predicted)
• 密度：
  1.292±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.31
• 重原子数：
  21.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  49.77
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  8-ethoxycarbonyl-3β-(4-chlorophenyl)-3α-hydroxy-8-azabicyclo[3.2.1]octane 在 盐酸 、 氢氧化钾 、 potassium carbonate 、 乙二醇 、 溶剂黄146 、 potassium iodide 作用下， 以 乙二醇二甲醚 为溶剂， 反应 14.5h， 生成
  参考文献：
  名称：

  Haloperidol: towards further understanding of the structural contributions of its pharmacophoric elements at D2-like receptors

  摘要：

  An attempt to understand the pharmacophore-relevant position of the alcoholic moiety in haloperidol and the contributions of other pharmacophoric elements led to the re-synthesis of its tropane analogue (compound 2). An analysis of the binding data suggests that haloperidol binds to the DA receptors with the OH group in the axial position and the OH group, while not essential for binding, enhances binding especially at the D2 receptor. It also became clear that shortening the butyrophenone chain not only reduces binding affinity at the DA receptors but eliminates subtype selectivity. (C) 2004 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2004.09.046
• 作为产物：
  描述：

  N-乙氧羰基-4-托品酮 、 4-氯苯基溴化镁 以 乙醚 为溶剂， 反应 12.0h， 以47%的产率得到8-ethoxycarbonyl-3β-(4-chlorophenyl)-3α-hydroxy-8-azabicyclo[3.2.1]octane
  参考文献：
  名称：

  The acute EPS of haloperidol may be unrelated to its metabolic transformation to BCPP +

  摘要：

  We have previously proposed that haloperidol's debilitating extrapyramidal symptoms (EPS) may be associated with its quaternary BCPP+ (an MPP+ like species) metabolite formed in vivo. However, recent work on D2 knock out mice suggests that haloperidol's EPS may be related to its potent D2 binding (K-i = 0.9 nM). In this study, we explore this question by synthesizing and testing an analogue (DS-27) that binds to D2 receptors with higher affinity than haloperidol, but cannot form quaternary metabolites. This study suggests that D2 affinity may be the primary underlying mechanism for acute catalepsy induction by haloperidol. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.07.015

文献信息

• Structure−Activity Relationships for a Novel Series of Dopamine D2-like Receptor Ligands Based on N-Substituted 3-Aryl-8-azabicyclo[3.2.1]octan-3-ol
  作者：Noel M. Paul、Michelle Taylor、Rakesh Kumar、Jeffrey R. Deschamps、Robert R. Luedtke、Amy Hauck Newman

  DOI：10.1021/jm800532x

  日期：2008.10.9

  Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K-i(D2R/MR) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2(L)R- or hD3R-transfected HEK 293 cells (31, K-i(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, K-i(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.
• Synthesis and evaluation of ligands for D2-like receptors: The role of common pharmacophoric groups
  作者：Donald M.N. Sikazwe、Nancy T. Nkansah、Ramazan Altundas、Xue Y. Zhu、Bryan L. Roth、Vincent Setola、Seth Y. Ablordeppey

  DOI：10.1016/j.bmc.2008.12.054

  日期：2009.2

  Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D-2-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that is, 40-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized agents at D-2-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors. Published by Elsevier Ltd.
• Synthesis and monoamine transporter affinity of 3α-arylmethoxy-3β-arylnortropanes
  作者：Harneet Kaur、Sari Izenwasser、Abha Verma、Dean Wade、Amy Housman、Edwin D. Stevens、David L. Mobley、Mark L. Trudell

  DOI：10.1016/j.bmcl.2009.10.087

  日期：2009.12

  A series of 3-arylnortrop-2-enes and 3 alpha-arylmethoxy-3 beta-arylnortropanes were synthesized and evaluated for binding affinity at monoamine transporters. The 3-(3,4-dichlorophenyl)nortrop-2-ene (6e) exhibited high affinity for the SERT (K-i = 0.3 nM). The 3 alpha-arylmethoxy-3 beta-arylnortropanes were generally SERT selective with the 3 alpha-(3,4-dichlorophenylmethoxy)-3 beta phenylnortrop-2-ene (7c) possessing subnanomolar potency (K-i = 0.061 nM). However, 3 alpha-(3,4-dichlorophenylmethoxy)-3 beta-phenylnortrop-2-ene (7b) exhibited high affinity at all three transporters [(DAT K-i = 22 nM), (SERT K-i = 6 nM) and (NET K-i = 101 nM)]. (C) 2009 Elsevier Ltd. All rights reserved.
• LANGBEIN, A.;MERZ, H.;SOBOTTA, R.;BAUER, R.;JENNEWEIN, H.;MIERAU, J.
  作者：LANGBEIN, A.、MERZ, H.、SOBOTTA, R.、BAUER, R.、JENNEWEIN, H.、MIERAU, J.

  DOI：——

  日期：——