摘要
阿片类镇痛药作用于体内μ、δ和κ三种阿片亚型受体，是中重度疼痛的主要治疗药物。但由于会产生呼吸抑制和成瘾性等严重副作用，其临床应用受到诸多限制。近年研究发现，δ受体对μ受体介导的生理效应存在着调节作用，可减少呼吸抑制和成瘾性等副作用的产生。因此，对μ和δ受体具有混合作用的配基已成为寻找新型强效低毒镇痛药的一个重要研究方向。美普他酚是一个上市的阿片类镇痛药，成瘾性低，呼吸抑制作用小，属于3-芳基氮杂环庚烷结构类型。我们的药理研究表明，右旋美普他酚(1a)是一个μ和δ受体的混合激动剂，具有协同增效的镇痛作用。因此，本论文以1a为先导物，运用“信使-位码”概念和计算机辅助设计方法，展开对3-芳基氮杂环庚烷类的结构改造研究。
第二章选取43个与1a具有相似结构的4-苯基哌啶类化合物，运用神经网络方法进行定量构效关系研究，并建立了初步的药效模型。认识到在4-苯基哌啶类化合物中，除了保守的碱性氮和苯环结构区域外，还分别存在一个疏水性和一个氢键受体型的药效基团。研究结果提示我们可在先导物的结构中引入相似的基团，就会增强配基对μ或δ受体的激动活性。
第三章在第二章研究的提示下，设计并合成了含有潜在疏水性药效基团的N-苯烷基取代衍生物。新化合物以1a为原料，经N-去甲基和N-烷基化制备。初步药理结果表明：氮上苄基取代物5是强效的μ/δ受体混合激动剂，活性相比1a分别提高了二十倍和三百倍；氮上苯乙基取代物6a为强效的δ受体选择性激动剂，活性优于公认的δ受体激动剂SNC80；6a的对映异构体6b则是μ受体选择性激动剂，活性优于吗啡，这对受体-配基的相互作用研究是具有理论意义的发现；目标化合物5和6a可作为有临床前景的候选药物进行研究。
第四章仍按照第二章研究的主旨，设计并合成了含有潜在氢键受体型药效基团的4-羟基衍生物。新化合物以已知中间体为原料，经两步还原，手性拆分和O-去甲基反应制备，并确定了四个差向异构体的绝对构型，优势构象和对映体过量值。初步药理结果显示，在3-芳基氮杂环庚烷的4位引入羟基未能显著增强对μ和δ受体的激动活性，但是4位羟基的引入可以对氮杂环庚烷构象起限制的作用，这为后续相关衍生物的构效关系研究打下了坚实的基础。
第五章则是基于第三、四章的研究结果，设计并合成了三个结构拼合化合物，希望达到协同增效或构象限制的作用。新化合物以光学单体16b和16c为原料，经N-去甲基，N-烷基化和O-去甲基制备。初步药理结果显示，药效基团拼合化合物22(3R,4R)是一个超强的μ受体激动剂，活性达12pM，与已知最强的μ受体激动剂羟甲芬太尼相当。构象限制化合物23b(3R,4S)和23e(3R,4R)分别是一个μ受体选择性激动剂和μ/δ受体混合激动剂，这说明3位苯环处于竖键是6a作用于δ受体的活性构象。22，23b和23c可作为具有临床前景的候选药物进行开发研究。第三至五章的结果结果指出，在3-芳基氮杂环庚烷结构中，氮上取代基对于配基活性和受体选择性有显著的影响，暗示受体上可能存在与之相对应的新“位码”受点，这为后续相关衍生物的结构优化指明了方向。
第六章根据经典δ受体选择性配基的药效模型，在3-芳基-4-羟基氮杂环庚烷结构的基础上设计并合成了含有潜在δ“位码”基团的4位酰氧基取代衍生物。新化合物以cis-16，trans-16或16c为原料，经酰化，O-去甲基制备。初步药理结果显示，无激动活性的母体化合物17c，在经苯乙酰基取代后，44是一个μ和δ受体的混合激动剂，对两种受体的激动活性比17c的前体1a分别了提高十五倍和六倍，其中μ受体激动活性略优于吗啡。这说明我们在3-芳基氮杂环庚烷的结构上找到了另一个可以调控配基活性和受体选择性的结构区域，44作为先导物为后续研究提供了新的探索空间。
第七章从4-羟基衍生物四个差向异构体的单晶结构出发，就七元环的构象特征和构象稳定性进行了初步的分析，发现在扭椅式构象中，以取代基处于七元环的β和i位为优先稳定的构象。此外，以单晶研究中意外发现的铵离子非对映异构现象为基础，结合核磁共振实验和理论计算方法，建立了两个扭椅式构象间“TC_1-T_1-TB_1-TB_2-T_2-TC_2”的相互转化路径。与已有七元环构象转化理论对比后，我们提出了一种对氮杂环庚烷等七元环结构的构象转化进行分类分析的方法。
第八章为化学和药理实验部分。总共涉及了55个中间体与目标化合物的合成，其中新化合物52个。4个3-芳基-4-羟基氮杂环庚烷差向异构体经单晶衍射确定绝对构型，并以手性HPLC测定对映体过量值。
Opioids are the most commonly prescribed analgesics to relieve moderate-to-severe pain. However, their clinical utilities are always limited by the serious side effects, such as respiratory depression and abuse potential. There has been increasing evidence that theδreceptor is involved in formation ofμ-mediated side effects, and opioids targeting onδreceptor may minimized these effects. So the compounds with mixedμ/δprofile are extremely valuable candidates for ideal analgesics without abuse potential. Meptazinol which belongs to 3-arylazepanes is a marketed analgesic drug with low addiction liability and respiratory depression. Bio-assays has revealed that (+)-meptazinol (1a) is aμand 8 mixed agonist, which may have a synergistic effect on its analgesic activities. And this is the start point of our research to explore novel opioids with mixedμ/δactivities, combined with the "message-address" concept and computer aided drug design.
In the second section, 43 4-phenylpiperidines which have similar structures with 1a were employed in a 2D-QSAR study by neural network method. A four-point pharmacophore model has been suggested: besides two conservative components of electronegative nitrogen and phenyl, the addition of a lipophilic group on the nitrogen and a hydrogen-bonding donor group on the piperidine tend to significantly enhance their analgesic activities. This result implies that the introduction of similar groups on la may improve their activities onμorδreceptors.
In the third section, based on the lipophilic pharmacophore proposed in the QSAR study, a series of N-phenylalkyl substituted derivatives were designed. Starting from 1a, the new compounds were prepared by N-demethylation and N-alkylation. The biological activity studies show that the N-benzyl substituted compound 5 is a potentμandδagonist, with 20 and 300 more fold than la, respectively. The N-phenethyl substituted compound 6a turns out to be an unexpectedδselective agonist, which is stronger then the well-knownδselective agonist SNC80. Interestingly, 6b, the enantiomer of 6a, is aμselective agonist activity and more potent than morphine. The discovery of these compounds is very instructive for the study of ligand-receptor interactions. 5 and 6a could be developed as clinical candidates.
In the fourth section, a hydroxy group enlightened by the QSAR study was introduced to the 4 position of meptazinol. The synthesis was started from a known intermediate, followed by two-step reduction, optical resolution and O-demethylation. The absolute configuration, dominant conformation and e.e. value were also determined. The biological activity studies show that the introduction of hydroxy group does not enhance their activities on all three receptors, but the flexible azepane ring was found been constrained after this modification. It provides a useful tool for the further SAR studies.
In the fifth section, in order to exert synergistic or conformation constrain effect, three compounds were designed using combination principles based on the results in third and fourth sections. It was found the new compound 22 (3R,4R) is an extremely potentμagonist (12pM), almost equivalent to the most potentμagonist ohmefentanyl. In addition, the constrained compound 23b (3R,4S) and 23c (3R,4R) turn out to be aμselective agonist andμ/δmixed agonist, which conforms the 3-aryl axial conformation is the bio-active conformation of 6a. 22, 23b and 23c could be developed as promising candidates for pain management. The study from third to fifth section indicates that the N-substitution in 3-arylazepanes may play an important role in their efficacy and receptor selectivity, which suggests a new address componentis on opioid receptors.
In the sixth section, according to the classic pharmacophores of 8 selective ligands, various lipophilic groups as potentialδ"address" component were introduced on the 4 position of meptazinol. The synthesis was started from cis-16, trans-16, or 16c, followed by alcylation and O-demethylation. The biological activity study suggests the compound 44 (3R,4R) with a phenylacetate substitution is aμandδagonist, which is 15 and 6 more fold than la and itsμagonist activity is stronger than morphine. This result provides a second structural component which is responsible for the efficacy and receptor selectivity of 3-arylazepanes.
In the seventh section, the conformations of the 3-aryl-4-hydroxy-azepanes were analysis based on their crystal structures. It was demonstrated the conformations with steric group substituted on theβor i position of the twist-chair form were slightly preferred. Based on the unique discovery of ammonium-driven diastereoisomerism in the crystal, a further NMR study and theoretical calculations were performed and presented a "TC_1-T_1-TB_1-TB_2-T_2-TC_2" step-wise mechanism of the conformational conversion. Finally, a general rule for predicting the prevalence conformations azepane-like seven membered rings and their transition pathway was proposed.
In the eighth section, the experimental part for the preparation of more than 55 intermediates and target compounds was presented. Among them, 52 are novel compounds. Furthermore, four stereoisomers of 3-aryl-4-hydroxy-azepanes were elucidated by X-ray crystallography, their enantiomers excess were determined by chiral HPLC as well.
引文
1. WHO, Achieveing balance in national opioids control policy: Guidelines for assessment [EB/OL]. http://www.painpolicy.wisc.edu/publicat/00whoabi/00whoabi. htm. 2007-03-12.
2. Gershell, L.; Goater, J., From the analys's couch - Making gains in pain[J]. Nature Reviews Drug Discovery, 2006, 5(11), 889-890.
3. Fisher, B.; Rehm, J., Illicit opioid use in the 21st century: witnessing a paradigm shift[J]? Addiction, 2007,102(4), 499-501.
4. Beckett, A.; Casy, A., Synthetic analgesics: stereochemical consideration[J]. Journal of Pharmacy and Pharmacology, 1954,6(12), 986-1001.
5. Kane, B. E.; Svensson, B.; Ferguson, D. M., Molecular recognition of opioid receptor ligands[J]. The AAPS Journal, 2006, 8(1), E126-137.
6. Aburi, M.; Smith, P. E., Modeling and simulation of the human delta opioid receptor[J]. Protein Science, 2004,13(8), 1997-2008.
7. Fowler, C. B.; Pogozheva, I. D.; LeVine, H.; Mosberg, H. I., Refinement of a??homology model of the mu-opioid receptor using distance constraints from intrinsic and engineered zinc-binding sites[J]. Biochemistry, 2004,43(27), 8700-8710.
8. Rasmussen, S. G. R; Choi, H. J.; Rosenbaum, D. M.; Kobilka, T. S.; Thian, F. S.; Edwards, R C; Burghammer, M; Ratnala, V. R. R; Sanishvili, R.; Fischetti, R. F.; Schertler, G. F. X.; Weis, W. I.; Kobilka, B. K., Crystal structure of the human beta(2) adrenergic G-protein-coupled receptor[J]. Nature, 2007,450(7168), 383-384.
9. Zimmerman, D. M.; Leander, J. D., Selective Opioid Receptor Agonists and Antagonists - Research Tools and Potential Therapeutic Agents[J]. Journal of Medicinal Chemistry, 1990,33(3), 895-902.
10. Abraham, D. J., Burger's Medicinal Chemistry & Drug Discovery[M]. 5 ed.; John Wiley & Sons: New York, 2003; Vol. 6, p 360-399.
11. Broccardo, M.; Improta, G, Antidiarrheal and colonic antipropulsive effects of spinal and supraspinal administration of the natural 8 opioid receptor agonist, [D-Ala2]deltorphin II, in the rat[J]. European Journal of Pharmacology, 1992,218(1), 69-73.
12. Torregrossa, M. M.; Jutkiewicz, E. M.; Mosberg, H. I.; Balboni, G; Watson, S. J.; Woods, J. H., Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats[J]. Brain Research, 2006,1069(1), 172-181.
13. Hill, M. P.; Hille, C. J.; Brotchie, J. M, Delta-opioid receptor agonists as a therapeutic approach in Parkinson's disease[J]. Drug News and Perspectives, 2000, 13(5), 261-268.
14. Barber, A.; Gottschlich, R., Novel developments with selective, non-peptidic kappa-opioid receptor agonists[J]. Expert Opinion on Investigational Drugs, 1997, 6(10), 1351-1368.
15. Mello, N. K.; Negus, S. S., Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys[J]. Journal of Pharmacology and Experimental Therapeutics, 1998,286(2), 812-824.
16. Schwyer, R., ACTH:a short introductory review[J]. Annals of New York Academy of Sciences, 1977,297(2), 3-26.
17. Chavkin, C; Goldstein, A., Specific receptor for the opioid peptide dynorphin: structure-activity relationships [J]. Proceedings of the National Academy of Sciences, 1981, 78(10), 6543-6547.
18. Portoghese, P. S.; Sultana, M.; Takemori, A. E., Design of peptidomimetic??delta-opioid receptor antagonists using the Message Address concept[J]. Journal of Medicinal Chemistry, 1990,33(6), 1714-1720.
19. Contet, C; Kieffer, B. L.; Befort, K., Mu opioid receptor: a gateway to drug addiction[J]. Current Opinion in Neurobiology, 2004,14(3), 370-378.
20. Pande, A. C; Pyke, R. E.; Greiner, M.; Wideman, G. L.; Benjamin, R.; Pierce, M. W., Analgesic efficacy of enadoline versus placebo or morphine in postsurgical pain[J]. Clinical Neuropharmacology, 1996,19(5), 451-456.
21. Negus, S. S.; Gatch, M. B.; Mello, N. K.; Zhang, X. Y; Rice, K., Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys[J]. Journal of Pharmacology and Experimental Therapeutics, 1998, 286(1), 362-375.
22. Gallantine, E. L.; Meert, T. F., A comparison of the antinociceptive and adverse effects of the μ-opioid agonist morphine and the 8-opioid agonist SNC80[J]. Basic & Clinical Pharmacology &Toxicology, 2005,97(1), 39-51.
23. Buschmann, H.; Christoph, T.; Friderichs, E.; Maul, C; Sundermann, B., Analgesics, from chemistry and pharmacology to clinical application[M]. Wiley-VCH: 2002;p 287-555.
24. Ananthan, S., Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics[J]. The AAPS Journal, 2006, 8(1), E118-125.
25. Vaught, J. L.; Takemori, A. E., Differential effects of Leucine and Methionine Enkephalin on Morphine-induced analgesia, acute tolerance and dependence [J]. The Journal of Pharmacology and Experimental Therapeutics, 1979,208(1), 86-90.
26. Lee, N. M.; Leybin, L.; Chang, J. K.; Loh, H. H., Opiate and peptide interaction: effect of enkephalin on morphine analgesia[J]. European Journal of Pharmacology, 1980,68(2), 181-185.
27. Vaught, J. L.; Rothman, R. B.; Westfall, T. C, Mu and delta receptors: Their role in analgesia and in the differential effects of opioid peptides on analgesia[J]. Life sciences, 1982,26(18), 1459-1464.
28. Holaday, J. W.; Hitzemann, R. J.; Currell, J.; Tortella, F. C; Belenky, G. L., Repeated electroconvulsive shock or chronic morphine increases the number of [3H]-(D-Ala2, D-Leu5)-enkephalin binding sites in rat brain membranes [J]. Life sciences, 1982,31(20-21), 2359-2362.
29. He, L.; Lee, N. M., Delta opioid receptor enhancement of mu opioid receptor-induced antinociception in spinal cord[J]. Journal of Pharmacology and??Experimental Therapeutics, 1998,285(3), 1181-1186.
30. Matthes, H. W. D.; Smadja, C; Valverde, O.; Vonesch, J. L.; Foutz, A. S.; Boudinot, E.; Denavit-Saubie, M.; Severini, C; Negri, L.; Roques, B. P.; Maldonado, R.; Kieffer, B. L., Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor[J]. Journal of Neuroscience, 1998,18(18), 7285-7295.
31. Horan, P.; Tallarida, R. J.; Haaseth, R. C; Matsunaga, T. O.; Hruby, V. j.; Porreca, F., Antinociceptive interactions of opioid delta receptor agonists with morphine in mice: supra- and sub-additivity[J]. Life sciences, 1992,50(20), 1535-1541.
32. Porreca, R; Takemori, A. E.; Sultana, M.; Portoghese, P. S.; Bowen, W. D.; Mosberg, H. I., Modulation of mu-mediated antinociception in the mouse involves opioid delta-2 receptors[J]. Journal of Pharmacology and Experimental Therapeutics, 1992,263(1), 147-152.
33. Malmberg, A. B.; Yaksh, T. L., Isobolographic and dose-response analyses of the interaction between intrathecal mu and delta agonists: effects of naltrindole and its benzofuran analog (NTB) [J]. Journal of Pharmacology and Experimental Therapeutics, 1992,263(1), 264-275.
34. Horan, P. J.; Mattia, A.; Bilsky, E. J.; Weber, S.; Davis, T. P.; Yamamura, H. I.; Malatynska, E.; Appleyard, S. M; Slaninova, J.; Misicka, A.; Lipkowski, A. W.; Hruby, V. J.; Porreca, R, Antinociceptive Profile of Biphalin, a Dimeric Enkephalin Analog[J]. Journal of Pharmacology and Experimental Therapeutics, 1993, 265(3), 1446-1454.
35. Yamazaki, M.; Suzuki, T.; Narita, M.; Lipkowski, A. W., The opioid peptide analogue biphalin induces less physical dependence than morphine[J]. Life sciences, 2001,69(9), 1023-1028.
36. Coop, A.; Rice, K. C, Role of delta-opioid receptors in biological processes[J]. Drug News and Perspectives, 2000,13,481-487.
37. Abdelhamid, E. E.; Sultana, M.; Portoghese, P. S.; Takemori, A. E., Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice[J]. Journal of Pharmacology and Experimental Therapeutics, 1991,258(1), 299-303.
38. Tisco, P. J.; Yaksh, T. L., Dose-dependent antagonism of spinal opioid receptor agonists by naloxone and naltrindole: additional evidence for delta-opioid receptor subtypes in the rat[J]. European Journal of Pharmacology, 1993,236(1), 89-96.
39. Miyamoto, Y.; Portoghese, P. S.; Takemori, A. E., Involvement of Delta-2 Opioid Receptors in Acute Dependence on Morphine in Mice[J]. Journal of Pharmacology and Experimental Therapeutics, 1993,265(3), 1325-1327.
40. Fundytus, M. E.; Schiller, P. W.; Shapiro, M.; Weltrowska, G.; Coderre, T. J., Attenuation of morphine tolerance and dependence with the highly selective 5-opioid receptor antagonist TIPP[ψ][J]. European Journal of Pharmacology, 1995, 286(1), 105-108.
41. Hepburn, M. J.; Little, P. J.; Gingras, J.; Kuhn, C. M., Differential effects of naltrindole on morphine-induced tolerance and physical dependence in rats[J]. Journal of Pharmacology and Experimental Therapeutics, 1997,281(3), 1350-1356.
42. Zhu, Y.; King, M. A.; Schuller, A. G. P.; Nitsche, J. F.; Reidl, M.; Elde, R. P.; Unterwald, E.; Pasternak, G.W.; Pintar, J. E., Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice[J]. Neuron, 1999,24(1), 243-252.
43. Zhao, G.M.; Wu, D. L.; Soong, Y.; Shimoyama, M.; Berezowska, I.; Schiller, P. W.; Szeto, H. H., Profound spinal tolerance after repeated exposure to a highly selective mu-opioid peptide agonist: Role of delta-opioid receptors[J]. Journal of Pharmacology and Experimental Therapeutics, 2002,302(1), 188-196.
44. Schiller, P. W.; Fundytus, M. E.; Merovitz, L.; Weltrowska, G.; Nguyen, T. M. D.; Lemieux, C.; Chung, N. N.; Coderre, T. J., The opioid mu agonist/delta antagonist DIPP-NH2[Psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats[J]. Journal of Medicinal Chemistry, 1999, 42(18), 3520-3526.
45. Uhl, G. R.; Childers, S. R.; Pasternak, G.W., An opiate-receptor gene family reunion[J]. Trends in Pharmacological Sciences, 1994,17(3), 89-93.
46. Chakrabarti, S.; Prather, P. L.; Yu, L.; Law, P. Y.; Loh, H. H., Expression of mu-opioid receptor in CHO cells:ability of mu-ligands to promote a-azidoanilide[32P]GTP labeling of multiple G protein subunits[J]. Journal of Neurochemistry 1995,64(6), 2534-2543.
47. Prather, P. L.; Loh, H. H.; Law, P. Y., Interaction of Delta-Opioid Receptors with Multiple G-Proteins-a Nonrelationship between Agonist Potency to Inhibit Adenylyl-Cyclase and to Activate G-Proteins[J]. Molecular Pharmacology, 1994, 45(5), 997-1003.
48. Alt, A.; Clark, M. J.; Woods, J. H.; Traynor, J. R., μ and δ opioid receptors activate the same G proteins in human neuroblastoma SH-SY5Y cells[J]. British Journal of Pharmacology, 2002,135(1), 217-225.
49. Malatynska, E., Recent advances in selective opioid receptor agonists and antagonists[J]. Medicinal Research Reviews, 2004,24(2), 182-212.
50. Martin, N. A.; Prather, P. L., Interaction of co-expressed mu- and delta-opioid receptors in transfected rat pituitary GH(3) cells[J]. Molecular Pharmacology, 2001, 59(4), 774-783.
51. Gomes, I.; Gupta, A.; Filipovska, J.; Szeto, H. H.; Pintar, J. E.; Devi, L. A., A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia[J]. Process of National Academy of Science, 2004,101(14), 5135-5139.
52. Breitwieser, G.E., G protein-coupled receptor oligomerization: implications for G protein activation and cell signaling[J]. Circulation Research, 2004, 9(23), 17-27.
53. Chang, K. J.; Rigdon, G. C.; Howard, J. L.; McNutt, R. W., A novel, potent and selective nonpeptidic delta-Opioid receptor agonist BW373U86[J]. Journal of Pharmacology and Experimental Therapeutics, 1993,267(2), 852-857.
54. Grundt, P.; Jales, A. R.; Traynor, J. R.; Lewis, J. W.; Husbands, S. M., 14-amino, 14-alkylamino, and 14-acylamino analogs of oxymorphindole. Differential effects on opioid receptor binding and functional profiles[J]. Journal of Medicinal Chemistry, 2003,46(8), 1563-1566.
55. Gao, P.; Larson, D. L.; Portoghese, P. S., Synthesis of 7-arylmorphinans. Probing the "address" requirements for selectivity at opioid delta receptors[J]. Journal of Medicinal Chemistry, 1998,41(16), 3091-3098.
56. Ananthan, S.; Kezar, H. S.; Carter, R. L.; Saini, S. K.; Rice, K. C.; Wells, J. L.; Davis, P.; Xu, H.; Dersch, C. M.; Bilsky, E. J.; Porreca, F.; Rothman, R. B., Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans[J]. Journal of Medicinal Chemistry, 1999,42(18), 3527-3538.
57. Wells, J. L.; Barlett, J. L.; Ananthan, S.; Bilsky, E. J., In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence[J]. Journal of Pharmacology and Experimental Therapeutics, 2001, 297(2), 597-605.
58. Ananthan, S.; Khare, N. K.; Saini, S. K.; Seitz, L. E.; Bartlett, J. L.; Davis, P.; Dersch, C. M.; Porreca, R; Rothman, R. B.; Bilsky, E. J., Identification of opioid ligands possessing mixed mu agonist/delta antagonist activity among
??pyridomorphinans derived from naloxone, oxymorphone, and hydropmorphone[J]. Journal of Medicinal Chemistry, 2004,47(6), 1400-1412.
59. Srivastava, S. K.; Husbands, S. M; Aceto, M. D.; Miller, C. N.; Traynor, J. R.; Lewis, J. W., 4 '-arylpyrrolomorphinans: Effect of a pyrrolo-N-benzyl substituent in enhancing delta-opioid antagonist activity[J]. Journal of Medicinal Chemistry, 2002, 45(2), 537-540.
60. King, M. A.; Su, W.; Nielan, C. L.; Chang, A. H.; Schutz, J.; Schmidhammer, H.; Pasternak, G. W., 14-Methoxymetopon, a very potent mu-opioid receptor-selective analgesic with an unusual pharmacological profiIe[J]. European Journal of Pharmacology, 2003,459(7), 203-209.
61. Lattanzi, R.; Spetea, M.; Schullner, F.; Rief, S. B.; Krassnig, R.; Negri, L.; Schmidhammer, H., Synthesis and biological evaluation of 14-alkoxymorphinans. 22. Influence of the 14-alkoxy group and the substitution in position 5 in 14-alkoxymorphinan-6-ones on in vitro and in vivo activities [J]. Journal of Medicinal Chemistry, 2005,48(9), 3372-3378.
62. Daniels, D. J.; Kulkarni, A.; Xie, Z. H.; Bhushan, R. G; Portoghese, P. S., A bivalent ligand (KDAN-18) containing delta-antagonist and k-agonist pharmacophores bridges delta(2) and k(l) opioid receptor phenotypes[J]. Journal of Medicinal Chemistry, 2005,48(6), 1713-1716.
63. Morphy, R.; Rankovic, Z., Designed multiple ligands. An emerging drug discovery paradigm[J]. Journal of Medicinal Chemistry, 2005,48(21), 6523-6543.
64. Daniels, D. J.; Lenard, N. R.; Etienne, C. L.; Law, P.-Y.; Roerig, S. C; Portoghese, P. S., Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series[J]. Process of National Academy of Science, 2005,102(52), 19208-19213.
65. Grundt, P.; Martinez-Bermejo, R; Lewis, J. W.; Husbands, S. M., Opioid binding and in vitro profiles of a series of 4-hydroxy-3-methoxyindolomorphinans. Transformation of a delta-selective ligand into a high affinity kappa-selective ligand by introduction of a 5,14-substituted bridge[J]. Journal of Medicinal Chemistry, 2003, 46(14), 3174-3177.
66. Zhang, A.; Li, R Y.; Ding, C. Y.; Yao, Q. Z.; Knapp, B. I.; Bidlack, J. M; Neumeyer, J. L., Synthesis and pharmacological evaluation of 6,7-indolo/thiazolo-morphinans-Further SAR of levorphanol[J]. Journal of Medicinal Chemistry, 2007, 50(11), 2747-2751.
67. Calderon, S. N.; Coop, A., SNC 80 and related delta opioid agonists[J]. Current Pharmaceutical Design, 2004,10(7), 733-742.
68. Varga, E. V.; Li, X.; Stropova, D.; Zalewska, T.; Landsman, R. S.; Knapp, R. J.; Malatynska, E.; Kawai, K.; A, M.; Nagase, H.; Calderon, S. N.; Rice, K.; Hruby, V. J.; Roeske, W. R.; Yamamura, H. I., The third extracellular loop of the human delta-opioid receptor determines the selectivity of delta-opioid agonists[J]. Molecular Pharmacology, 1996,50(6), 1619-1624.
69. Bishop, M. J.; Garrido, D. M; Boswell, G E.; Collins, M. A.; Harris, P. A.; McNutt, R. W.; O'Neill, S. J.; Wei, K.; Chang, K. J. 3-(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: Potent, non-peptidic agonists of both mu and delta opioid receptors[J]. Journal of Medicinal Chemistry, 2003,46(4), 623-633.
70. Gengo, P. J.; Pettit, H. O.; O'Neill, S. J.; Wei, K.; McNutt, R.; Bishop, M. J.; Chang, K. J., DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1 -piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A mixed opioid agonist with potent antinociceptive activity [J]. Journal of Pharmacology and Experimental Therapeutics, 2003,307(3), 1221-1226.
71. Gengo, P. J.; Pettit, H. O.; O'Neill, S. J.; Su, Y. F.; McNutt, R.; Chang, K. J., DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-l-piperazinyl)-3-h ydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. II. A mixed opioid agonist with potent antinociceptive activity and limited effects on respiratory function[J]. Journal of Pharmacology and Experimental Therapeutics, 2003,307(3), 1227-1233.
72. Zimmerman, D. M.; Nickander, R.; Horng, J. S.; Wong, D. T., New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series[J]. Nature, 1978,275(5678), 332-333.
73. Zimmerman, D. M.; Leander, J. D.; Cantrell, B. E.; Reel, J. K.; Snoddy, J.; Mendelsohn, L. G; Johnson, B. G; Mitch, C. H., Structure-Activity-Relationships of Trans-3,4-Dimethyl-4-(3-Hydroxy- phenyl)Piperidine Antagonists for Mu-Opioid and Kappa-Opioid Receptors[J]. Journal of Medicinal Chemistry, 1993, 36(20), 2833-2841.
74. Su, Y.-R; McNutt, R. W; Chang, K.-J., Delta-Opioid Ligands Reverse Alfentanil-Induced Respiratory Depression but Not Antinociception[J]. Journal of Pharmacology and Experimental Therapeutics, 1998,287(3), 815-823.
75. Boyd, R. E.; Carson, J. R.; Codd, E. E.; Gauthier, A. D.; Neilson, L. A.; Zhang,??S.-P., Synthesis and binding affinities of 4-diarylaminotropanes, a new class of delta opioid agonists [J]. Bioorganic & Medicinal Chemistry Letters, 2000, 10(10), 1109-1111.
76. Thomas, j. B.; Atkinson, R. N.; Rothman, R. B.; Burgess, J. P.; Mascarella, S. W.; Dersch, C. M.; Xu, H.; Carroll, F. L., 4-[(8-Alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-diethylbenz-amides: high affinity, selective ligands for the delta opioid receptor illustrate factors important to antagonist activity[J]. Bioorganic & Medicinal Chemistry Letters, 2000,10(11), 1281-1284.
77. Carson, J. R.; Coats, S. J.; Codd, E. E.; Dax, S. L.; Lee, J.; Martinez, R. P.; McKown, L. A.; Neilson, L. A.; Pitis, P. M; Wu, W. N.; Zhang, S. P., N-alkyl-4-1(8-azabicyclo[3.2.1]-oct-3-ylidene) phenylmethyl]-benzamides, mu and delta opioid agonists: a mu address[J]. Bioorganic & Medicinal Chemistry Letters, 2004,14(9), 2113-2116.
78. Coats, S. J.; Schulz, M. J.; Carson, J. R.; Codd, E. E.; Hlasta, D. J.; Pitis, P. M.; Stone, D. J.; Zhang, S. P.; Colburrn, R. W.; Dax, S. L., Parallel methods for the preparation and SAR exploration of N-ethyl-4-[(8-alkyl-8-aza-bicyclo[3.2.1]-oct-3-ylidene)-aryl-methyl]-benzamides, powerful mu and delta opioid agonists[J]. Bioorganic & Medicinal Chemistry Letters, 2004,14(22), 5493-5498.
79. Cheng, K.; Kim, I. J.; Lee, M. J.; Adah, S. A.; Raymond, T. J.; Bilsky, E. J.; Aceto, M. D.; May, E. L.; Harris, L. S.; Coop, A.; Dersch, C. M.; Rothman, R. B.; Jacobson, A. E.; Rice, K. C, Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a mu-agonist delta-antagonist and delta-inverse agonists[J]. Organic & Biomolecular Chemistry, 2007, 5(8), 1177-1190.
80. Hiebel, A. C; Lee, Y. S.; Bilsky, E.; Giuvelis, D.; Deschamps, J. R.; Parrish, D. A.; Aceto, M. D.; May, E. L.; Harris, L. S.; Coop, A.; Dersch, C. M.; Partilla, J. S.; Rothman, R. B.; Cheng, K. J.; Jacobson, A. E.; Rice, K. C, Probes for narcotic receptor mediated phenomena. 34. Synthesis and structure-activity relationships of a potent mu-agonist delta-antagonist and an exceedingly potent Antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series[J]. Journal of Medicinal Chemistry, 2007, 50(16), 3765-3776.
1. Hoskin, P. J.; Hanks, G. W., Opioid agonist-antagonist drugs in acute and chronic pain states[J]. Drugs, 1991,41(3), 326-344.
2. Green, D., Current concepts concerning the mode of action of meptazinol as an analgesic[J]. Postgraduate Medical Journal, 1983, (Supple-1), 9-12.
3. Holmes, B.; Ward, A., Meptazinol: a review of its pharmacodynamic and pharmacokineic properties and therapeutic efficacy [J]. Drugs, 1985, 30(4), 285-312.
4. Zimmerman, D. M; Nickander, R.; Horng, J. S.; Wong, D. T., New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series[J]. Nature, 1978,275(5678), 332-333.
5. Oshlack, B.; Chasin, M.; Huang, H. P. Melt-extrudeo orally administrable opioid formulations[P]. WO Pat: 9614058A1,1996-05-17.
6. Mauskop, A. Analgesic composition for treatment of migraine headaches[P]. WO Pat: 9803179A1,1998-01-29.
7. Li, W.; Hao, J. L.; Tang, Y; Chen, Y.; Qiu, Z. B., Comparative studies of X-ray determined meptazinol enantiomers with analgesic pharmacophore[J]. Acta Pharmacologica Sinica, 2005,26(3), 334-338.
8. Tzschentke, T. M.; Bruckmann, W.; Friderichs, E., Lack of sensitization during place conditioning in rats is consistent with the low abuse potential of tramadol[J]. Neuroscience Letters, 2002, 329(1), 25-28.
9. Zhang, H.; Zhang, Y Q.; Qiu, Z. B., Inhibitory effect of intrathecal meptazinol on carrageenan-induced thermal hyperalgesia in rats[J]. Neuroscience Letters, 2004, 356(1), 9-12.
10．陈燕．美普他酚合成、拆分及光学活性体的研究[D]．复旦大学，上海，硕士学位论文，2004．
11. Abraham, D. J., Burger's Medicinal Chemistry & Drug Discovery[M]. John Wiley & Sons: New York, 2003; Vol. 6, p 376-381.
12. Casy, A. F.; Parfitt, R. T., Opioid analgesics chemistry and receptors[M]. Plenum: New York, 1986.
13. Casy, A. R; Dewar, G. H., The steric factor in medicinal chemistry. Dissymmetric probes of pharmacological receptors[M]. Plenum: New York, 1993; p 429-548.
14. Thomas, j. B.; Atkinson, R. N.; Rothman, R. B.; Burgess, J. P.; Mascarella, S. W.; Dersch, C. M.; Xu, H.; Carroll, F. L, 4-[(8-Alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-diethylbenz-amides: high affinity, selective ligands for the delta opioid receptor illustrate factors important to antagonist activity [J]. Bioorganic & Medicinal Chemistry Letters, 2000,10(11), 1281-1284.
15. Herz, A.; Akil, H.; Simon, E. J., Opioids I, Handbook of experimental pharmacology. Springer-Verlag: Berlin[M], 1993; Vol. 104/I, p 773-797.
16. Casy, A. R, Probable conformations of some reversed esters of meperidine as solutes in water. Conformational factors in 4-phenylpiperidine analgetics [J]. Journal of Medicinal Chemistry, 1968,11(1), 188-191.
17. Portoghese, P. S.; Alreja, B. D.; Larson, D. L., Allyprodine analogues as receptor probes. Evidence that phenolic and nonphenolic ligands interact with different subsites on identical opioid receptors [J]. Journal of Medicinal Chemistry, 1981,24(7), 782-787.
18. Portoghese, P. S., A New Concept on the Mode of Interaction of Narcotic Analgesics with Receptors[J]. Journal of Medicinal Chemistry, 1965, 8(5), 609-616.
19. D.M. Zimmerman; J. D. Leander; B.E. Cantrell; J.K. Reel; J.Snoddy; L.G.??Mendelsohn; B.G. Johnson; Mitch, C. H., Structure-activity relationships of trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine antagonists for μ and κ opioid receptors[J]. Journal of Medicinal Chemistry, 1993, 36(20), 2833-2841.
20. D.M. Zimmerman; J.S. Gidda; B.E. Cantrell; D.D. Schoepp; B.G. Johnson; Leander, J. D., Discovery of a Potent, Peripherally Selective trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonist for the Treatment of Gastrointestinal Motility Disorders[J]. Journal of Medicinal Chemistry, 1994, 37(15), 2262-2265.
21. Friedman, J. D.; Dello-Buono, F. A., Opioid antagonists in the treatment of opioid-induced constipation and pruritus[J]. The Annals of Pharmacotherapy 2001, 35(1), 85-91.
22. Thomas, J. B.; Mascarella, S. W.; Rothman, R. B.; Partilla, J. S.; Xu, H.; McCullough, K. B.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I., Investigation of the N-Substituent Conformation Governing Potency and μ Receptor Subtype-Selectivity in (+)-(3R,4R)-Dimethyl-4- (3-hydroxyphenyl)-piperidine Opioid Antagonists[J]. Journal of Medicinal Chemistry, 1998,41(11), 1980-1990.
23. Thomas, J. B. F., M. J.; Cooper, J. B.; Rothman, R. B.; Mascarella, S. W.; Xu, H.; Partilla, J. S.; Dersch, C. M.; McCullough, K. B.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I., Identification of an Opioid kappa Receptor Subtype-Selective N-Substituent for (+)-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine[J]. Journal of Medicinal Chemistry, 1998,41(26), 5188-5197.
24. Thomas, J. B. A., R. N.; Rothman, R. B.; Fix, S. E.; Mascarella, S. W.; Vinson, N. A.; Xu, H.; Dersch, C. M.; Lu, Y. -F.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I., Identification of the First trans-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine Derivative To Possess Highly Potent and Selective kappa Opioid Receptor Antagonist Activity [J]. Journal of Medicinal Chemistry, 2001,44(17), 2687-2690.
25. Ong, H. H. O.-i., T.; May, E. L., Phenylmorphan agonistsantagonists[J]. Journal of Medicinal Chemistry, 1974,17(1), 133-134.
26. Thomas, J. B. Z., X.; Mascarella, S. W.; Rothman, R. B.; Dersch, C. M.; Partilla, J. S.; Flippen-Anderson, J. L.; George, C. F.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I., N-Substituted 9β-Methyl-5-(3-hydroxyphenyl)morphans Are Opioid Receptor Pure Antagonists[J]. Journal of Medicinal Chemistry, 1998, 41(21), 4143-4149.
27. Thomas, J. B. Z., L.; Navarro, H. A.; Carroll, F. I., Highly Potent and Selective??Phenylmorphan-Based Inverse Agonists of the Opioid delta Receptor[J]. Journal of Medicinal Chemistry, 2006,49(18), 5597-5609.
28. Dondio, G R., S.; Eggleston, D. S.; Artico, M.; Petrillo, P.; Petrone, G; Visentin, L.; Farina, C; Vecchietti, V.; Clarke, G D., Discovery of a Novel Class of Substituted Pyrrolooctahydroisoquinolines as Potent and Selective delta Opioid Agonists, Based on an Extension of the Message-Address Concept[J]. Journal of Medicinal Chemistry, 1997,40(20), 3192-3198.
29. Dondio, G, Development of novel pain relief agents acting through the selective activation of the delta-opioid receptor[J]. II Farmaco, 2000, 55(3), 178-180.
30．陈凯先；蒋华良；嵇汝运，计算机辅助药物设计-原理、方法和应用[M]．上海科学技术出版社：中国，2000；p 141-164．
31．徐筱杰；侯廷军；乔学斌；章威，计算机辅助药物分子设计pM]．化学工业出版社：2004；p 267-268．
32. Aoyama, T.; Suzuki, Y.; Ichikawa, H., Neural networks applied to structure-activity relationships[J]. Journal of Medicinal Chemistry, 1990, 33(3), 905-908.
33. Douali, L.; Villemin, D.; Cherqaoui, D., Neural Networks: Accurate Nonlinear QSAR Model for HEPT Derivatives[J]. Journal of Chemical Information and Computer Sciences, 2003,43(4), 1200-1207.
34. Chiu, T. L.; So, S. S., Development of Neural Network QSPR Models for Hansch Substituent Constants. 2. Applications in QSAR Studies of HIV-1 Reverse Transcriptase and Dihydrofolate Reductase Inhibitors [J]. Journal of Chemical Information and Computer Sciences, 2004,44(1), 154-160.
35. Agtonovic-Kustrin, S.; Beresford, R., Basic concepts of artificial neural network (ANN) modeling and its application in pharmaceutical research[J]. Journal of pharmaceutical and biomedical analysis, 2000,22(5), 717-727.
36. Janssen, P. A. J.; Eddy, N. B., Compounds Related to Pethidine--IV. New Genaral Chemical Methods of Increading the Analgesic Activity of Pethidine[J]. Journal of Medicinal Chemistry, 1960,2(1), 31-45.
37. Wolff, M. E., Burger's Medicinal Chemistry and Drug Design[M]. 3rd ed.; John Wiley & Sons: New York 1995; Vol. 1, p 497.
38．许禄，化学计量学方法[M]．科学出版社：北京，1995．
39. Todeschini, R.; Consonni, V., Handbook of molecular descriptors[M]. Weinheim: Germany, 2000.
40. Hemmateenejad, B.; Akhond, M.; Miri, R.; Shamsipur, M, Genetic Algorithm Applied to the Selection of Factors in Principal Component-Artificial Neural Networks: Application to QSAR Study of Calcium Channel Antagonist Activity of 1,4-Dihydropyridines (Nifedipine Analogous) [J]. Journal of Chemical Information and Computer Sciences, 2003,43(4), 1328-1334.
41. ISIS/Base is distributed from MDL information systems[CP].
42. Gasteiger, J.; Rudolph, C.; Sadowski, J., Automatic generation of 3D-atomic coordinates for organic molecules[J]. Tetrahedron Computer Methodology, 1990, 3(6), 537-547.
43. SYBYL 6.9 Tripos Inc., H. R., St. Louis, MO 63144[CP].
44. http://146.107.217.178/online.html[CP].
45. Hypercube Inc., http://www.hyper.com[CP].
46. ACD Lab Inc., http://www.acdlabs.com[CP].
47. Frisch, M. J.; al, e. Gaussian 03, Revision C02[CP], Gaussian, Inc., Wallingford CT, 2004.
48. Zhang, T, Leave-One-Out Bounds for Kernel Methods[J]. Neural Computation, 2003,15(6), 1397-1437.
49. http://www.informatik.uni-stuttgart.de/ipvr/bv/projekte/snns/snns.html[CP].
50. Tang, Y.; Chen, K. X.; Jiang, H. L.; Ji, R. Y., QSAR/QSTR of fluoroquinolones: an example of simultaneous analysis of multiple biological activities using neural network method. European Journal of Medicinal Chemistry 1998, 33, (7-8), 647-658.
51. Golbraikh, A.; Tropsha, A., Beware of q2[J]. Journal of Molecular Graphics and Modelling, 2002,20(4), 269-276.
52. Andrea, T. A.; Kalayeh, H., Applications of neural networks in quantitative structure-activity relationships of dihydrofolate reductase inhibitors[J]. Journal of Medicinal Chemistry, 1991, 34(9), 2824-2836.
53. So, S. S.; Richards, W. G., Application of neural networks: quantitative structure-activity relationships of the derivatives of 2,4-diamino-5-(substituted-benzyl)pyrimidines as DHFR inhibitors[J]. Journal of Medicinal Chemistry, 1992, 35(17), 3201-3207.
54. Andrea, T. A.; Kalayeh, H., Applications of neural networks in quantitative structure-activity relationships of dihydrofolate reductase inhibitors[J]. Journal of Medicinal Chemistry, 1991, 34(9), 2824-2836.
55. Tang, Y.; Wang, H. W.; Chen, K. X.; Ji, R. Y., QSAR of 3-methylfentanyl
derivatives studied with neural networks method[J]. Acta Pharmacologica Sinica,
1995,16(1), 26-32.
1. Wang, X. H.; Tang, Y; Xie, Q.; Qiu, Z. B., QSAR study of 4-phenylpiperidine derivatives as mu opioid agonists by neural network method [J]. European Journal of Medicinal Chemistry, 2006,41(2), 226-232.
2．陈燕．美普他酚合成、拆分及光学活性体的研究[D]．复旦大学，上海，硕士学位论文，2004．
3. Smissman, E. E.; Makriyannis., Azodicarboxylic acid esters as dealkylating agents[J]. Journal of Organic Chemistry, 1973, 38(9), 1652-1657.
4. Pecherer, B. S., J.; Brossi, A., Synthesis and characteristics of various 3-benzazocines, a class of potential analgesics[J]. Helvetic Chimica Acta, 1970, 53(4), 763-770.
5. Hobson, J. D.; McCluskey, J. G.., Cleavage of tertiary bases with phenyl chloroformate: the reconversion of 21-deoxyajmaline into ajmaline[J]. Journal of Chemical Society (C), 1967, 2015-2017.
6. Abdel-Monem, M. M.; Porgoghese, P. S., N-Demethylation of morphine and structurally related compounds with chloroformate esters[J]. Journal of Medicinal Chemistry, 1972,15(2), 208-210.
7. Calderon, S. N.; Coop, A., SNC 80 and related delta opioid agonists[J]. Current Pharmaceutical Design, 2004,10(7), 733-742.
8. Subramanian, G; Paterlini, M. G; Portoghese, P. S.; Ferguson, D. M, Molecular docking reveals a novel binding site model for fentanyl at the μ opioid receptor [J]. Journal of Medicinal Chemistry, 2000,43(3), 381-391.
9. Cheng, K.; Kim, I. J.; Lee, M. J.; Adah, S. A.; Raymond, T. J.; Bilsky, E. J.; Aceto, M. D.; May, E. L.; Harris, L. S.; Coop, A.; Dersch, C. M.; Rothman, R. B.; Jacobson, A. E.; Rice, K. C, Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a mu-agonist delta-antagonist and delta-inverse agonists[J]. Organic & Biomolecular Chemistry, 2007, 5(8), 1177-1190.
10. Hiebel, A. C; Lee, Y. S.; Bilsky, E.; Giuvelis, D.; Deschamps, J. R.; Parrish, D. A.; Aceto, M. D.; May, E. L.; Harris, L. S.; Coop, A.; Dersch, C. M.; Partilla, J. S.; Rothman, R. B.; Cheng, K. J.; Jacobson, A. E.; Rice, K. C, Probes for narcotic receptor mediated phenomena. 34. Synthesis and structure-activity relationships of a potent mu-agonist delta-antagonist and an exceedingly potent Antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethyImorphan series[J]. Journal of Medicinal Chemistry, 2007, 50(16), 3765-3776.
1. Wang, X. H.; Tang, Y.; Xie, Q.; Qiu, Z. B., QSAR study of 4-phenylpiperidine derivatives as mu opioid agonists by neural network method[J]. European Journal of Medicinal Chemistry, 2006,41(2), 226-232.
2. Abraham, D. J., Burger's Medicinal Chemistry & Drug Discovery[M]. John??Wiley & Sons: New York, 2003; Vol. 6, p 376-381.
3．郝敬来；李炜；谢琼；陈燕；仇缀百，1-甲基-3-乙基-3-(3’-羟基苯基)-六氢-1H-氮杂卓盐酸盐的合成[J]．复旦学报，2005，32(2)，173-177．
4. Carey, F. A.; Sundberg, R. J., Advanced organic chemistry[M]. 4 ed.; Kluwer Academic / Plenum Publishers: New York, 2001; Vol. Part B: Reactions and synthesis.
5. Simth, M. B.; March, J., March's advanced organic chemistry: reactions, mechanisms and structure[M]. 5th ed.; John Wiley & Sons: New York, 2001; p 533.
6. Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K., Azetidines and bisazetidines. Their synthesis and use as the key intermediates to enantiomerically pure diamines, amino alcohols, and polyamines[J]. Journal of Organic Chemistry, 1991, 56(18), 5263-5277.
7. Caijo, F.; Mosset, P.; Gree, R.; Audinot-Bouchez, V; Boutin, J.; Renard, P.; Caignard, D. H.; Dacquet, C, Synthesis of aromatic analogs of 8(S)-HETE and their biological evaluation as activators of the PPAR nuclear receptors[J]. European Journal of Orgranic Chemistry, 2006, (9), 2181-2196.
8. Smith, A. B.; Wood, J. L.; Keenan, T. P.; Liverton, N.; Visnick, M., General photoisomerization approach to trans-benzobicyclo[5.1.0]octenes: synthetic and mechanistic studies[J]. Journal of Organic Chemistry, 1994, 59(22), 6652-6666.
9. Wang, Y. Z.; Metz, P., Resolution of methyl nonactate[J]. Tetrahedron-asymmetry, 2000,11(19), 3995-3999.
10. Jiang, J. L.; Li, A. H.; Jang, S. Y; Chang, L.; Melman, N.; Moro, S.; J, X. D.; Lobkovsky, E. B.; Clardy, J. C; Jacobson, K. A., Chiral resolution and stereospecificity of 6-phenyl-4-phenylehtynyl-1,4-dihydropyridines as selective A3 adenosine receptor antagonists [J]. Journal of Medicinal Chemistry, 1999, 42(16), 3055-3065.
11. Gupta, A. K.; Kazlauskas, R. J., Calibration plots to aid determination of high enantiomeric purity using chiral lanthanide shift reagents [J]. Tetrahedron-asymmetry, 1992,3(2), 243-246.
12．苏克曼；江向东；菜水洪，1H-NMR测定手性化合物的对映体过量[J]．光谱实验室，1999，16(6)，604-610．
13. Farrugia, L. J., ORTEP-3 for Windows - a version of ORTEP-III with a Graphical User Interface (GUI) [J]. Journal of Applied Crystallography, 1997, 30, 565-565.
14. Birnbaum, G. I.; Buchanan, G. W.; Morin, F. G, Geometry of cycloheptane??conformers: crystal structure of l-dimethylphosphono-l-hydroxycycloheptane[J]. Journal of American Chemical Society, 1977,99(20), 6652-6656.
15. Ourhriss, N.; Giorgi, M; Mazoir, N.; Benharref, A., Absolute configuration and conformational disorder of a tricyclic thiosemicarbazone derivative[J]. Acta Crystallographica Section C - Crystal Structure Communications, 2005, 61, 0699-701.
16. Carroll, F. I., 2002 Medicinal chemistry division award address: monoamine transporters and opioid receptors[J]. Targets for addiction therapy. Journal of Medicinal Chemistry, 2003,46(10), 1775-1794.
1. Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.; Malfroot, T., A new reagent for the selective, high-yield N-dealkylation of tertiary amines: improved syntheses of naltrexone and nalbuphine[J]. Journal of Organic Chemistry, 1984, 49(11), 2081-2082.
2. Hengeveld, J. E.; Gupta, A. K.; Kemp, A. H.; Thomas, A. V., Facile N-demethylation of erythromycins[J]. Tetrahedron Letters, 1999,40(13), 2497-2500.
3. Thomas, J. B.; Zhang, L.; Navarro, H. A.; Carroll, F. I., Highly potent and selective phenylmorphan-based inverse agonists of the opioid 8 receptor[J]. Journal of Medicinal Chemistry, 2006,49(18), 5597-5069.
1. Quock, R. M.; Burkey, T. H.; Varga, E.; Hosohata, Y.; Hosohata, K.; Cowell, S. M.; Slate, C. A.; Ehlert, F. J.; Roeske, W. R.; Yamamura, H. I., The 5-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy[J]. Pharmacological Reviews, 1999,51(3), 503-532.
2. Jutkiewicz, E. M, The antidepressant-like effects of delta-opioid receptor agonists[J]. Molecular Interventions, 2006, 6(3), 162-169.
3. Kaczor, A.; Matosiuk, D., Non-peptide opioid receptor ligands-recent advances. Part I -agonists[J]. Current Medicinal Chemistry, 2002,9(17), 1567-1589.
4. Calderon, S. N.; Coop, A., SNC80 and related 5 agonists[J]. Current Pharmaceutical Design, 2004,10(7), 733-742.
5. Dondio, G.; Ronzoni, S.; Farina, C; Graziani, D.; Parini, C; Petrillo, P.; Giardina, G A. M., Selective 5 opioid receptor agonists for inflammatory and neuropathic pain[J]. Il Farmaco 2001, 56(1-2), 117-119.
6. Mclamore, S.; Ullrich, T.; Rothman, R. B.; Xu, H.; Dersch, C; Coop, A.; Davis, P.; Porreca, F.; Jacobson, A. E.; Rice, K. C, Effect of N-Alkyl and N-Alkenyl Substituents in Noroxymorphindole, 17-Substituted-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7:2',3'-indolomorphinans, on Opioid Receptor Affinity, Selectivity, and Efficacy[J]. Journal of Medicinal Chemistry, 2001,44(9), 1471-1474.
7. Schwyer, R., ACTH:a short introductory review[J]. Annals of New York Academy of Sciences, 1911,297(2), 3-26.
8. Kane, B. E.; Svensson, B.; Ferguson, D. M., Molecular recognition of opioid receptor ligands[J]. The AAPS Journal, 2006, 8(1), E126-137.
9. Portoghese, P. S.; Sultana, M; Takemori, A. E., Design of peptidomimetic .delta. opioid receptor antagonists using the message-address concept[J]. Journal of Medicinal Chemistry, 1990,33(6), 1714-1720.
10. Dondio, G; Ronzoni, S.; Eggleston, D. S.; Artico, M.; Petrillo, P.; Petrone, G; Visentin, L.; Farina, C; Vecchietti, V.; Clarke, G D., Discovery of a novel class of substituted pyrrolooctahydroisoquinolines as potent and selective 8 opioid agonist, based on an extension of the message-address concept[J]. Journal of Medicinal Chemistry, 1997,40(20), 3192-3198.
11. Calderon, S. N.; Rothman, R. B.; Porreca, F.; Mcnutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Rice, K. C, Probes for Narcotic Receptor Mediated Phenomena. 19. Synthesis of (+)-4-[(.alpha.R)-.alpha.-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80): A Highly Selective, Nonpeptide delta Opioid Receptor Agonist[J]. Journal of Medicinal Chemistry, 1994,37(14), 2125-2128.
12. Thomas, J. B.; Herault, X. M.; Rothman, R. B.; Burgess, J. P., (±)-4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding for the delta opioid receptor[J]. Bioorganic & Medicinal Chemistry Letters, 1999, 9(13), 3053-3056.
13. Thomas, J. B.; Herault, X. M.; Rothman, R. B.; Atkinson, R. N.; Burgess, J. P.; Mascarella, S. W.; Dersch, C. M.; Xu, H.; Flippen-Anderson, J. L.; George, C. F.;??Carroll, F. I., Factors Influencing Agonist Potency and Selectivity for the 8 Opioid Receptor Are Revealed in Structure-Activity Relationship Studies of the 4-[(N-Substituted-4-piperidinyl)arylamino]-N,N-diethylbenzamides[J]. Journal of Medicinal Chemistry, 2001,44(6), 972-987.
14. Wei, Z. Y.; Brown, W.; Takasaki, B.; Plobeck, N.; Delorme, D.; Zhou, F.; Yang, H.; Jones, P.; Gawell, L.; Gagnon, H.; Schmidt, R.; Yue, S. Y; Walpole, C; Payza, K.; St-onge, S.; Lavarre, M.; Godbout, C; Jakob, A.; Butterworth, J.; Kamassah, A.; Morin, P. E.; Projean, D.; Ducharme, J.; Roberts, E., N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: A Novel, Exceptionally Selective, Potent 8 Opioid Receptor Agonist with Oral Bioavailability and Its Analogues[J]. Journal of Medicinal Chemistry, 2000,43(21), 3895-3905.
15. Nortey, S. O.; Baxter, E. W.; Codd, E. E.; Zhang, S. P.; Reitz, A. B., Piperazinyl benzamidines: Synthesis and affinity for the delta opioid receptor[J]. Bioorganic & Medicinal Chemistry Letters, 2001,11(13), 1741-1743.
16. Huang, P.; Kim, S.; Loew, G H., Development of a common 3D pharmacophore for delta-opioid recognition from peptides and non-peptides using a novel computer program[J]. Journal of Computer Aidded Molecular Design, 1991,11(1), 21-28.
17. Coop, A.; Jacobson, A. E., The LMC delta opioid recognition pharmacophore: comparison of SNC80 and oxymorphindole[J]. Bioorganic & Medicinal Chemistry Letters, 1999,9(3), 357-362.
18. Dondio, G; Ronzoni, S.; Petrillo, P.; DesJarlais, R. L.; Raveglia, L. F., Pyrrolooctahydroisoquinolines as potent and selective ° opioid receptor ligands: SAR analysis and docking studies[J]. Bioorganic & Medicinal Chemistry Letters, 1997, 7(23), 2967-2972.
19. Chaturvedi, K.; Jiang, X.; Christoffers, K. H.; Chinen, N.; Bandari, P.; Raveglia, L. F.; Ronzoni, S.; Dondio, G; Howell, R. D., Pharmacological profiles of selevtive non-peptide delta opioid receptor ligands[J]. Molecular Brain Research, 2000, 80(2), 166-176.
20. Tacke, R.; Kornek, T.; Heinrich, T.; Burschka, C; Penka, M.; Pulm, M; Keim, C; Mutschler, E.; Lambrecht, G, Syntheses and pharmacological characterization of achiral and chiral enantiopure C/Si/Ge-analogous derivatives of the muscarinic antagonist cycrimine: a study on C/Si/Ge bioisosterism[J]. Journal of Organometallic Chemistry, 2001,640(1-2), 140-165.
1. Li, W.; Wang, X. H.; Lau, C. Y; Tang, Y; Xie, Q.; Qiu, Z. B., Conformational re-analysis of (+)-meptazinol: an opioid with mixed analgesic pharmacophores[J]. Acta Pharmacologica Sinica, 2006,27(9), 1247-1252.
2．伊莱尔，E．L．；威伦，S．H．；多伊尔，M．P．，基础有机立体化学[M]．科学出版社：北京，2005；p 383-443．
3． 假旋转(pseudorotation)：根据IUPAC的定义(http：∥goldbook．iupac．org／P04934．html)，在某些对称性分子中，通过旋转产生的新构象可以与其初始构象完全重叠，这个过程就可以称为“假旋转”。这一概念最早应用于环戊烷的构象研究[EB]。
4. Bocian, D. F.; Pickett, H. M.; Rounds, T. C; Strauss, H. L., Conformations of cycloheptane[J]. Journal of American Chemical Society, 1975,97(4), 687-695.
5. Entrena, A.; Campos, J. M; Gallo, M. A.; Espinosa, A., Rules for predicting the conformational behavior of saturated seven-membered heterocycles[J]. ARKIVOC, 2005,4,88-108.
6. Hans, J.; Day, R. 0.; Howe, L.; Holmes, R. R., Conformational comparison of a seven-membered ring in tri- and pentacoordinated geometries of oxygen-containing phosphorus compounds. Solution NMR behavior of seven- and eight- membered rings in oxyphosphoranes[J]. Inorganic Chemistry, 1992,31(7), 1279-1285.
7. Espinosa, A.; Gallo, M. A.; Entrena, A.; Gomez, J. A., Theoretical conformational analysis of seven-membered rings. 6. Perhydroazepine[J]. Journal of Molecular Structure, 1994,326,249-260.
8. Entrena, A.; Campos, J. M; Gomez, J. A.; Gallo, M. A.; Espinosa, A., A new systematization of the conformational behavior of seven-membered rings. Isoclinal anomeric and related orientations[J]. Journal of Organic Chemistry, 1997, 62(2), 337-349.
9. Hendrickson, J. B., Molecular geometry. I. Machine computation of the common rings[J]. Journal of American Chemical Society, 1961, 83(20), 4537-4547.
10. Hendrickson, J. B., Molecular geometry. II. Methyl-cyclohexanes and cycloheptanes[J]. Journal of American Chemical Society, 1962, 84(17), 3355-3359.
11. Prelog, V.; Helmchen, G, Basic Principles of the CIP-System and Proposals for a Revision[J]. Angewandte Chemie International Edition in English, 1982, 21(8), 567-583.
12. Kuzmin, V. E.; Kamalov, G. L.; Sharygin, V. N., Conformational variety of saturated seven-membered rings[J]. Journal of Structural Chemistry, 1983, 24(5), 746-750.
13. Hendrickson, J. B., Molecular geometry. VII. Modes of interconversion in the medium rings[J]. Journal of American Chemical Society, 1967, 89(26), 7047-7061.
14. Sharygin, V. N.; Kamalov, G L., Conformational transitions differing from pseudorotation in saturated seven-membered rings[J]. Journal of Structural Chemistry, 1985,26(2), 153-157.
15. Entrena, A.; Jaime, C; Espinosa, A.; Gallo, M. A., Theoretical (MM2) conformational analysis of 1,4-dioxepane[J]. Journal of Organic Chemistry, 1989, 54(7), 1745-1748.
16. Majchrzak, M. W.; Kotezko, A.; Guryn, R., Chair-boat interconversions in cyclic seven-membered amides and related structures [J]. Tetrahedron, 1981, 37(6), 1075-1080.
17. Glaser, R.; Hug, P.; Drouin, M.; Michel, A., Solution- and solid-state stereochemistry of (-)-alpha-lobeline hydrochloride and hydrobromide, a??respiratory-stimulant drug[J]. Journal of the Chemical Society-Perkin Transactions 2,1992,(7), 1071-1079.
18. Glaser, R.; Bernstein, M. A., ~1H and ~(13)C NMR studies on the conformation ofN-methyl diastereomers of (+)-glaucine hydrotrifluoroacetate, an aporphine alkaloidsalt[J]. Journal of the Chemical Society-Perkin Transactions 2, 1991, (12),2047-2053.
19．伊莱尔，E．L．；威伦，S．H．；多伊尔，M．P，基础有机立体化学[M]．科学出版社：北京，2005；p 83-86．
20. Wuthrich, K.; Billeter, M.; Braun, W., Pseudo-structures for the 20 common amino-acids for use in studies of protein conformations by measurements on intramolecular proton proton distance constraints with NMR[J]. Journal of Molecular Biology, 1983,169(4), 949-961.
21. Frish, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; et al Gaussian 03[CP], Gaussian, Inc: Wallingford CT, 2004.
22. Bucourt, R. Topics in Stereochemistry[M]. John Wiley & Sons: New York, 1974; Vol. 8, The torsion angle concept in conformational analysis, p 156.
1．陈燕．美普他酚合成、拆分及光学活性体的研究[D]．复旦大学，上海，硕士学位论文，2004．
2. Liu, J.G.; Prather, P.L. Chronic Exposure to u-Opioid Agonists Produces Constitutive Activation of u-Opioid Receptors in Direct Proportion to the Efficacy of the Agonist Used for Pretreatment[J]. Molecular Pharmacology, 2001, 60(1), 53-62.
