cyclic[Gly-Gln-Ala-Arg]

• 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: cyclic[Gly-Gln-Ala-Arg]
• 英文别名: cyclo[Ala-Arg-Gly-Gln]；3-[(2S,5S,8S)-8-[3-(diaminomethylideneamino)propyl]-5-methyl-3,6,9,12-tetraoxo-1,4,7,10-tetrazacyclododec-2-yl]propanamide
• 化学式: C₁₆H₂₈N₈O₅
• 分子量: 412.449
• InChiKey: RDMRCQGDYXDUJZ-GUBZILKMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.8
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  224
• 氢给体数：
  7
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  BOC-甘氨酸 、 N-叔丁氧羰基-L-丙氨酸 、 Boc-L-谷氨酰胺 、 N-叔丁氧羰基-N'-甲苯磺酰基-L-精氨酸 以20%的产率得到cyclic[Gly-Gln-Ala-Arg]
  参考文献：
  名称：

  Bioactive Peptidic Analogues and Cyclostereoisomers of the Minimal Antinociceptive Histogranin Fragment-(7−10)

  摘要：

  Novel analogues of the minimal antinociceptive histogranin (HN) fragment Gly(7)-Gln-Gly-Arg(10), in which amino acids in positions 8, 9, and 10 were replaced by lipophilic amino acids and corresponding D-amino acid residues in combination with N- to C-terminal cyclization, were synthesized and tested in various animal models of pain. All synthetic compounds were potent and efficacious analgesics in the mouse writhing test. Cyclic [-Gly-Ala-Tyr-D-Arg-] (9) and cyclic [-Gly p-Cl-Phe-Tyr-D-Arg-] (10) were the most potent analgesics, being 17 and 135 times as potent as HN, respectively (AD50 of 1.37 and 0.17 nmol/mouse icv, as compared with 23 nmol/mouse for HN). The times of action of compounds 9 and 10 were also much improved with half-maximal effects still being observed 60 min and >90 min after their administration, respectively, as compared with 8.1 min for the parent peptide HN-(7-10) and 22.1 min for HN. At analgesic doses, compounds 9 and 10 were devoid of motor effect as assessed by the mouse rotarod assay. As already observed with HN, compounds 9 (10 nmol/rat; i.t.) and 10 (0.5 nmol/rat; i.t.) were effective in blocking persistent inflammatory pain in the formalin test and hyperalgesia induced by intraplantar administration of complete Freund adjuvant. In addition, the analgesic effects evoked by compounds 9 (10 nmol/mouse; icv) and 10 (1 mumol/kg; i.v.) in the mouse writhing test and compound 9 (10 mnol/mouse; icv) in the mouse tail flick assay were similarly antagonized by the dopamine D-2 receptor antagonist raclopride (1 nmol/mouse; icv) but not the opiate antagonist naloxone (1 nmol/mouse; icv). Finally, the various cyclic compounds competed with the binding of [H-3]raclopride in rat brain membrane preparations. Their ability to compete with the binding of the D-2 ligand correlated well with their potency in alleviating pain in the mouse writhing test (r = 0.95). These results indicate that the analgesic activity of the minimal active core in HN can be improved by changes that favor its interaction with the dopamine D-2 receptor.

  DOI：

  10.1021/jm0300734

文献信息

• Bioactive Peptidic Analogues and Cyclostereoisomers of the Minimal Antinociceptive Histogranin Fragment-(7−10)
  作者：Hoang-Thanh Le、Irma B. Lemaire、Annie-Kim Gilbert、François Jolicoeur、Simon Lemaire

  DOI：10.1021/jm0300734

  日期：2003.7.1

  Novel analogues of the minimal antinociceptive histogranin (HN) fragment Gly(7)-Gln-Gly-Arg(10), in which amino acids in positions 8, 9, and 10 were replaced by lipophilic amino acids and corresponding D-amino acid residues in combination with N- to C-terminal cyclization, were synthesized and tested in various animal models of pain. All synthetic compounds were potent and efficacious analgesics in the mouse writhing test. Cyclic [-Gly-Ala-Tyr-D-Arg-] (9) and cyclic [-Gly p-Cl-Phe-Tyr-D-Arg-] (10) were the most potent analgesics, being 17 and 135 times as potent as HN, respectively (AD50 of 1.37 and 0.17 nmol/mouse icv, as compared with 23 nmol/mouse for HN). The times of action of compounds 9 and 10 were also much improved with half-maximal effects still being observed 60 min and >90 min after their administration, respectively, as compared with 8.1 min for the parent peptide HN-(7-10) and 22.1 min for HN. At analgesic doses, compounds 9 and 10 were devoid of motor effect as assessed by the mouse rotarod assay. As already observed with HN, compounds 9 (10 nmol/rat; i.t.) and 10 (0.5 nmol/rat; i.t.) were effective in blocking persistent inflammatory pain in the formalin test and hyperalgesia induced by intraplantar administration of complete Freund adjuvant. In addition, the analgesic effects evoked by compounds 9 (10 nmol/mouse; icv) and 10 (1 mumol/kg; i.v.) in the mouse writhing test and compound 9 (10 mnol/mouse; icv) in the mouse tail flick assay were similarly antagonized by the dopamine D-2 receptor antagonist raclopride (1 nmol/mouse; icv) but not the opiate antagonist naloxone (1 nmol/mouse; icv). Finally, the various cyclic compounds competed with the binding of [H-3]raclopride in rat brain membrane preparations. Their ability to compete with the binding of the D-2 ligand correlated well with their potency in alleviating pain in the mouse writhing test (r = 0.95). These results indicate that the analgesic activity of the minimal active core in HN can be improved by changes that favor its interaction with the dopamine D-2 receptor.