2-(isoquinoline-3-carboxamido)acetic acid | 1236037-48-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(isoquinoline-3-carboxamido)acetic acid
• 英文别名: (isoquinoline-3-carbonyl)glycine；2-(Isoquinoline-3-carbonylamino)acetic acid
• CAS: 1236037-48-1
• 化学式: C₁₂H₁₀N₂O₃
• 分子量: 230.223
• InChiKey: PZURRDUNVQLWGD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  79.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(isoquinoline-3-carboxamido)acetic acid 、 6α-naltrexamine dihydrochloride 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 甲醇 为溶剂， 反应 0.25h， 以72%的产率得到17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[2-(isoquinoline-3-carboxamido)acetamido]morphinan
  参考文献：
  名称：

  Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

  摘要：

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2015.02.055
• 作为产物：
  描述：

  异喹啉-3-甲酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.25h， 生成 2-(isoquinoline-3-carboxamido)acetic acid
  参考文献：
  名称：

  Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

  摘要：

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2015.02.055

文献信息

• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSÉS CHIMIQUES
  申请人：ISIS INNOVATION

  公开号：WO2015092412A1

  公开（公告）日：2015-06-25

  A compound which is a pyridine or isoquinoline derivative of formula (I), or a pharmaceutically acceptable salt thereof, which is useful in the inhibition of γ- butyrobetaine hydroxylase (BBOX). The compounds are particularly useful in treatment of cardiovascular disease and diabetes. (I)

  一种化合物，是公式(I)的吡啶或异喹啉衍生物，或其药学上可接受的盐，用于抑制γ-丁酰甜菜碱羟化酶（BBOX）。这些化合物在治疗心血管疾病和糖尿病方面特别有用。
• NON-PEPTIDYL, POTENT, AND SELECTIVE MU OPIOID RECEPTOR ANTAGONISTS AND THEIR USE IN TREATING OPIOID ADDICTION AND OPIOID INDUCED CONSTIPATION
  申请人：Virginia Commonwealth University

  公开号：US20140371255A1

  公开（公告）日：2014-12-18

  Selective, non-peptide antagonists of the mu opioid receptor (MOR) and methods of their use are provided. The antagonists may be used, for example, to identify MOR agonists in competitive binding assays, and to treat conditions related to addiction in which MOR is involved, e.g. heroin, prescription drug and alcohol addiction, as well as in the treatment of opioid induced constipation (OIC).

  提供了选择性的、非肽类的μ阿片受体（MOR）拮抗剂及其使用方法。这些拮抗剂可用于识别竞争性结合测定中的MOR激动剂，以及治疗与MOR有关的成瘾症状，例如海洛因、处方药物和酒精成瘾，以及治疗因阿片类药物引起的便秘（OIC）。
• Substituierte Isochinolin-3-Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
  申请人：Hoechst Marion Roussel Deutschland GmbH

  公开号：EP0911340A2

  公开（公告）日：1999-04-28

  Neue Isochinolin-3-carbonsäureamide der Formel I in welcher R1 Wasserstoff oder Chlor, R2 Wasserstoff, Alkyl, Alkoxy, Chlor, Trifluormethyl, Hydroxy, oder Benzyloxy, das gegebenenfalls substituiert ist, oder Fluoralkoxy der Formel O-[CH2]x-CfH(2f+1-g)Fg mit x = 0 und 1, f = 1 - 5 und g = 1 bis (2f+1), R3 Wasserstoff, Alkyl, Alkoxy, Fluor, Chlor, Cyano, Trifluormethyl, Hydroxy, oder Benzyloxy, das gegebenenfalls substituiert ist, oder Fluoralkoxy der obigen Formel, R4 und R5 Wasserstoff, Alkyl, Fluor, Chlor, Brom, Trifluormethyl, Cyano, Alkoxy, oder Fluoralkoxy der obigen Formel bedeuten, einschließlich der physiologisch wirksamen Salze, sind starke Prolyl-4-hydroxylase-Inhibitoren sind, die nicht Steatose bewirken.

  一种新型异喹啉-3-甲酰胺，其式为 I 其中 R1 是氢或氯，R2 是氢、烷基、烷氧基、氟、氯、氰基、三氟甲基、羟基或苄氧基，后者任选被取代，或式 O-[CH2]x-CfH(2f+1-g)Fg 的氟烷氧基，其中 x = 0 和 1，f = 1 - 5，g = 1 至 (2f+1)，R3 是氢、烷基、烷氧基、氟、氯、氰基、三氟甲基、羟基或苄氧基，后者任选被取代，或上式的氟烷氧基，R4 和 R5 是氢、烷基、氟、氯、氰基、三氟甲基、羟基或苄氧基，后者任选被取代，或上式的氟烷氧基、或任选取代的苄氧基，或上式的氟烷氧基，R4 和 R5 为氢、烷基、氟、氯、溴、三氟甲基、氰基、烷氧基或上式的氟烷氧基，包括生理活性盐，是不会导致脂肪变性的强脯氨酰-4-羟化酶抑制剂。
• Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function
  作者：Yunyun Yuan、Orgil Elbegdorj、Irina O. Beletskaya、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmcl.2013.07.043

  日期：2013.9

  17-Cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1'- or 4'-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQanalogues retained low efficacy at the MOR compared to NAQin the S-35-GTP[gamma S] binding assays while electron-withdrawing groups at 1'-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1'- or 4'-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation. Published by Elsevier Ltd.
• [EN] NON-PEPTIDYL, POTENT, AND SELECTIVE MU OPIOID RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES NON PEPTIDIQUES, PUISSANTS ET SÉLECTIFS DES RÉCEPTEURS OPIOÏDES MU
  申请人：UNIV VIRGINIA COMMONWEALTH

  公开号：WO2010083384A9

  公开（公告）日：2010-10-14