Boc-Tic-Gly-NH-Ph | 403652-18-6

• 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: Boc-Tic-Gly-NH-Ph
• 英文别名: tert-butyl (3S)-3-[(2-anilino-2-oxoethyl)carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 403652-18-6
• 化学式: C₂₃H₂₇N₃O₄
• 分子量: 409.485
• InChiKey: WUUWQHLBUJJPGU-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  87.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 Boc-Tic-Gly-NH-Ph 以96%的产率得到TFA*H-Tic-Gly-NH-Ph
  参考文献：
  名称：

  Synthesis and opioid activity of N,N-Dimethyl-Dmt-Tic-NH-CH(R)-R′ analogues: acquisition of potent δ antagonism

  摘要：

  N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R' series of compounds produced no significant affect on the high delta-opioid receptor affinity (K-i = 0.035-0.454 nM), but dramatically decreased that for the p-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R'): phenyl (Ph) (5'-8') elicited a greater reduction in mu-affinity (40-70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i) a loss of delta-agonism coupled with the appearance of potent 6 antagonism (4'-7') (pA(2) = 8.14-9.47), while 1 exhibited only a 160-fold decreased delta agonism (1') and the delta antagonism of 8 enhanced > 10-fold (pA(2) = 10.62, 8'); and (ii) a consistent loss of P-affinity resulted in enhanced delta-opioid receptor selectivity. With the exception of compound 1, the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent delta-selective antagonists. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2003.09.039
• 作为产物：
  描述：

  N-叔丁氧羰基-(S)-1,2,3,4-四氢异喹啉-3-羧酸 、 以85%的产率得到Boc-Tic-Gly-NH-Ph
  参考文献：
  名称：

  Synthesis and opioid activity of N,N-Dimethyl-Dmt-Tic-NH-CH(R)-R′ analogues: acquisition of potent δ antagonism

  摘要：

  N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R' series of compounds produced no significant affect on the high delta-opioid receptor affinity (K-i = 0.035-0.454 nM), but dramatically decreased that for the p-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R'): phenyl (Ph) (5'-8') elicited a greater reduction in mu-affinity (40-70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i) a loss of delta-agonism coupled with the appearance of potent 6 antagonism (4'-7') (pA(2) = 8.14-9.47), while 1 exhibited only a 160-fold decreased delta agonism (1') and the delta antagonism of 8 enhanced > 10-fold (pA(2) = 10.62, 8'); and (ii) a consistent loss of P-affinity resulted in enhanced delta-opioid receptor selectivity. With the exception of compound 1, the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent delta-selective antagonists. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2003.09.039

文献信息

• Evaluation of the Dmt−Tic Pharmacophore:  Conversion of a Potent δ-Opioid Receptor Antagonist into a Potent δ Agonist and Ligands with Mixed Properties
  作者：Gianfranco Balboni、Remo Guerrini、Severo Salvadori、Clementina Bianchi、Daniela Rizzi、Sharon D. Bryant、Lawrence H. Lazarus

  DOI：10.1021/jm010449i

  日期：2002.1.1

  Analogues of the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore were prepared to test the hypothesis that a "spacer" and a third aromatic center in opioid peptides are required to convert a delta-antagonist into ligands with delta-agonist or with mixed delta-antagonist/mu-agonist properties. Potent delta-agonists and bifunctional compounds with high delta- and mu-opioid receptor affinities were obtained by varying the spacer length [none, NH-CH2, NH-CH2-CH2, Gly-NH-CH2] and C-terminal aromatic nucleus [1H-benzimidazole-2-yl, phenyl (Ph) and benzyl groups]: C-terminal modification primarily affected,mu-opioid receptor affinities, which increased maximally 1700-fold relative to the prototype delta-antagonist H-Dmt-Tic-NH2 and differentially modified bioactivity. In the absence of a spacer (1), the analogue exhibited dual delta-agonism (pEC(50), 7.28) and delta-antagonism (pA(2), 7.90). H-Dmt-Tic-NH-CH2-1H-benzimidazol-2-yl (Bid) (2) became a highly potent delta-agonist (pEC(50), 9.90), slightly greater than deltorphin C (pEC(50), 9.56), with mu-agonism (pE(50), 7.57), while H-Dmt-Tic-Gly-NH-CH2-Bid (4) retained potent delta-antagonism, (pA2, 9.0) but with an order of magnitude less mu-agonism. Similarly, H-Dmt-Tic-Gly-NH-Ph (5) had nearly equivalent high mu-agonism (pEC(50), 8.52) and mu-agonism (pEC(50), -8.59), while H-Dmt-TicGly-NH-CH2-Ph (6) whose spacer was longer by a single methylene group exhibited potent delta-antagonism. (pA2, 9.25) and very high mu-agonism (pEC(50), 8.57). These data confirm that the distance between the Dmt-Tic pharmacophore and a third aromatic nucleus is an important criterion in converting Dint-Tic from a highly potent delta-antagonist into a potent delta-agonist or into ligands with mixed delta- and,mu-opioid properties.
• Synthesis and opioid activity of N,N-Dimethyl-Dmt-Tic-NH-CH(R)-R′ analogues: acquisition of potent δ antagonism
  作者：Gianfranco Balboni、Severo Salvadori、Remo Guerrini、Lucia Negri、Elisa Giannini、Sharon D Bryant、Yunden Jinsmaa、Lawrence H Lazarus

  DOI：10.1016/j.bmc.2003.09.039

  日期：2003.12

  N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R' series of compounds produced no significant affect on the high delta-opioid receptor affinity (K-i = 0.035-0.454 nM), but dramatically decreased that for the p-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R'): phenyl (Ph) (5'-8') elicited a greater reduction in mu-affinity (40-70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i) a loss of delta-agonism coupled with the appearance of potent 6 antagonism (4'-7') (pA(2) = 8.14-9.47), while 1 exhibited only a 160-fold decreased delta agonism (1') and the delta antagonism of 8 enhanced > 10-fold (pA(2) = 10.62, 8'); and (ii) a consistent loss of P-affinity resulted in enhanced delta-opioid receptor selectivity. With the exception of compound 1, the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent delta-selective antagonists. Published by Elsevier Ltd.