N^α-Boc-(S-p-MeBzl)-D-penicillamine | 115962-34-0

• 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: N^α-Boc-(S-p-MeBzl)-D-penicillamine
• 英文别名: Boc-D-Pen(pMeBzl)-OHdcha；(2S)-3-methyl-3-[(4-methylphenyl)methylsulfanyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid
• CAS: 115962-34-0
• 化学式: C₁₈H₂₇NO₄S
• mdl: MFCD00080280
• 分子量: 353.483
• InChiKey: SIBYHJVDFRKDDV-AWEZNQCLSA-N

物化性质

• 沸点：
  504.2±50.0 °C(Predicted)
• 密度：
  1.145±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.555
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N^α-Boc-(S-p-MeBzl)-D-penicillamine 在 乙酸铵 、 ammonium hydroxide 、 potassium hexacyanoferrate(III) 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 生成 3>DPDPE
  参考文献：
  名称：

  [L-Ala3]DPDPE: A New Enkephalin Analog with a Unique Opioid Receptor Activity Profile. Further Evidence of .delta.-Opioid Receptor Multiplicity

  摘要：

  To investigate delta-opioid receptor topography near the 3-position of [D-Pen(2),D-Pen(5)] enkephalin (DPDPE), a series of small-group 3-position analogs of DPDPE have been synthesized and assayed for binding potencies and in vitro biological activities. L-Amino acid substitutions at this position are highly favored over D-amino acid substitutions, with the smallest, [L-Ala(3)]DPDPE(DPADPE), being the most favored in the series investigated. [L-Ala(3)]DPDPE is nearly as delta-potent and more delta-selective in both rat brain binding (18 nM vs [H-3][p-ClPhe(4)]DPDPE and mu/delta = 610) and peripheral bioassays (12 nM in the MVD and GPI/MVD = 4500) when compared to DPDPE (8.5 nM, mu/delta = 73 and 4.1 nM, GPI/MVD = 1800, respectively). Whereas DPDPE is a potent analgesic when given icv, [L-Ala(3)]DPDPE is only a weak analgesic. However, [L-Ala(3)]DPDPE has been found to antagonize DPDPE, but not Deltorphin II, in a moderately potent (pA(2) = 5.7) and selective fashion in vivo. Thus, [L-Ala(3)]DPDPE is a fairly potent agonist at peripheral delta receptors and is a moderately potent (mixed) antagonist of delta(1) receptors in the brain. It appears that [L-Ala(3)]DPDPE does not interact in any significant manner with delta(2) or mu receptors in the brain.

  DOI：

  10.1021/jm00037a007

文献信息

• Ring substituted and other conformationally constrained tyrosine analogs of [cyclic] [D-Pen2,D-Pen5]enkephalin with .delta.-opioid receptor selectivity
  作者：Geza Toth、K. C. Russell、Geoffrey Landis、Thomas H. Kramer、Lei Fang、Richard Knapp、Peg Davis、Thomas F. Burks、Henry I. Yamamura、Victor J. Hruby

  DOI：10.1021/jm00091a006

  日期：1992.6

  opioid receptor selectivity. Of the beta-methyl-substituted Tyr1 analogues, [(2S,3R)-beta-MeTyr1]DPDPE was the most potent and the delta receptor selective. The results with substitution of beta-MeTyr or Hat instead of Tyr also demonstrate that topographical modification in a conformationally restricted ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have

  构象受限的含环状二硫键的δ阿片受体选择性脑啡肽类似物[D-Pen2，D-Pen5]脑啡肽（DPDPE）通过2'（CH3）和3'（I，OCH3，NO2，NH2）环取代和被β-甲基构象约束的β-甲基酪氨酸衍生物置于1位。这些类似物的效价和选择性通过在小鼠输精管上的生物测定（MVD，δ受体测定）和豚鼠回肠（GPI，mu受体测定）测定，以及在大鼠脑中使用[3H] CTOP（ μ配体）和[3H] [p-ClPhe4] DPDPE（δ配体）。类似物在结合测定和生物测定中显示出高度可变的效力。Hammett常数为正的芳香环取代基的效能降低，而具有负Hammett约束的取代基则增加了阿片受体的效价。基于结合的最有效和最具选择性的化合物是[2'-MeTyr1] DPDPE（结合分析中IC50 = 0.89 nM，选择性比为1310）。含6-羟基-2-氨基四氢-2-羧酸的类似物[Hat1] DPDPE在两种测
• Probing the Stereochemical Requirements for Receptor Recognition of δ Opioid Agonists through Topographic Modifications in Position 1
  作者：Xinhua Qian、Mark D. Shenderovich、Katalin E. Kövér、Peg Davis、Robert Horváth、Teresa Zalewska、Henry I. Yamamura、Frank Porreca、Victor J. Hruby

  DOI：10.1021/ja954241w

  日期：1996.1.1

  A series of side-chain constrained tyrosine derivatives, 2‘,6‘-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-d-Pen2-Gly-Phe-d-Pen5-OH) and deltorphin I (DELT I, Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing

  一系列侧链受限的酪氨酸衍生物 2',6'-二甲基-β-甲基酪氨酸 (TMT) 已被设计并整合到高选择性 δ 阿片类激动剂 DPDPE (Tyr-d-Pen2-Gly- Phe-d-Pen5-OH）和德尔托芬 I（DELT I，Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2）。分离的 TMT 残基的分子力学计算和 DMSO 中含有 TMT1 的肽的核磁共振 (NMR) 研究表明，TMT 的四种立体异构体中的每一种都有利于侧链 χ1 扭转角的一个特定旋转异构体。因此，将四个 TMT 异构体替换为 Tyr1 使我们能够通过芳香侧链的三个交错旋转异构体、gauche (-)、反式和 gauche (+) 进行系统构象扫描，并探索受体在侧链构象的关系。
• Newly discovered stereochemical requirements in the side-chain conformation of .delta. opioid agonists for recognizing opioid .delta. receptors
  作者：Xinhua Qian、Katalin E. Koever、Mark D. Shenderovich、Bih-Show Lou、Aleksandra Misicka、Teresa Zalewska、Robert Horvath、Peg Davis、E. J. Bilsky

  DOI：10.1021/jm00038a004

  日期：1994.6

  Topographic design of peptide ligands using specialized topographically constrained amino acids can provide new insights into the stereochemical requirements for delta opioid receptors. A highly constrained tyrosine derivative, (2S,3S)-beta-methyl-2',6'-dimethyltyrosine [(2S,3S)-TMT], was prepared by asymmetric synthesis and incorporated in [D-Pen2,D-Pen5] enkephalin (delta 1) and Deltorphin I (delta

  使用专门的地形约束氨基酸对肽配体进行地形设计可以为δ阿片受体的立体化学需求提供新的见解。通过不对称合成制备了高度受限的酪氨酸衍生物（2S，3S）-β-甲基-2'，6'-二甲基酪氨酸[（2S，3S）-TMT]，并​​掺入了[D-Pen2，D-Pen5]脑啡肽（δ1）和Deltorphin I（δ2）。结合测定和生物测定的结果表明，两种类似物（3和4）对δ阿片受体的作用非常不同。进一步的药理评估表明，它们实际上主要分别与delta 1和delta 2受体亚型相互作用。这些结果以及使用NMR和计算机辅助建模的构象研究，
• Systemic analgesic activity and .delta.-opioid selectivity in [2,6-dimethyl-Tyr1, D-Pen2, D-Pen5]enkephalin
  作者：Donald W. Hansen、Awilda Stapelfeld、Michael A. Savage、Melvin Reichman、Donna L. Hammond、Ronald C. Haaseth、Henry I. Mosberg

  DOI：10.1021/jm00082a008

  日期：1992.2

  The cyclic peptide [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr1 residue of [D-Pen2,D-Pen5]enkephalin (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the delta-opioid receptor and a 35-fold increase in potency at the mu-receptor while substantial delta-receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 was inactive following systemic administration of doses as high as 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an ED50 of 2.6 mg/kg. These results demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyr1 with DMT.
• Design, Synthesis, and Biological Properties of highly Potent Cyclic Dynorphin A Analogs. Analogs Cyclized between Positions 5 and 11
  作者：Jean-Philippe Meyer、Nathan Collins、Feng-Di Lung、Peg Davis、Teresa Zalewska、Frank Porreca、Henry I. Yamamura、Victor J. Hruby

  DOI：10.1021/jm00049a010

  日期：1994.11

  We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A(1-11)-NH2, exhibited unexpected selectivities for the kappa and mu receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A(1-11)-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A(1-11)-NH2, [D-Leu(5)]Dyn A(1-11)-NH2, and [D-Lys(11)]Dyn A(1-11)-NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys(5), D-Cys(11)] Dyn A(1-11)-NH2, c[Cys(5), L- or D-Pen(11)]Dyn A(1-11)-NH2, c[Pen(5), L-Pen(11)]Dyn A(1-11)-NH2 and c[Pen(5), L- or D-Cys(11)]Dyn A(1-11)-NH2, retained the same affinity and selectivity (vs the mu and delta receptors) as the parent compound Dyn A(1-11)-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at kappa opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the kappa, mu, or delta central receptors.