新型镇痛剂的合成、构效关系及生物学研究
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摘要
疼痛已成为影响人们生活质量的一个重要病症。新型非阿片类镇痛药物的研究与开发是目前镇痛药物研究的难点与热点。本论文设计合成了一系列具有镇痛活性的芳烷哌嗪类新化合物,通过其镇痛活性与结构关系研究,优选出候选药物分子,研究了候选药物分子的初步毒性、量效关系、依赖性与动物药代动力学,为寻找具有自主知识产权的镇痛候选新药奠定基础。
1、定向设计5个系列芳烷哌嗪衍生物,对设计的化合物进行了合成研究工作,优化了合成线路与工艺。共设计合成6类化合物,合成了62个化合物,其中51个化合物未见文献报道,9个化合物虽有CAS号,但无性状描述。所得化合物结构经核磁共振、质谱确证。
2、建立动物镇痛药物筛选模型-热板法与扭体法,用此模型对合成的62个化合物进行镇痛活性的筛选,筛选结果表明有20个化合物有显著的镇痛活性。根据筛选结果,发现并总结了芳烷哌嗪类化合物的结构与镇痛活性的关系:1)苯基哌嗪苯乙酮类化合物具有良好镇痛活性,苯基上有供电子基取代时活性增强,吸电子取代基降低活性;2)苯基被其它杂芳基取代时活性降低;3)苯基与哌嗪之间增加一个碳原子活性保持,但镇静作用增加;苯基上供电子基团取代有利于活性增加,吸电子基团取代活性降低甚至消失;4)羰基肟化时活性显著降低;羰基被亚甲基取代时活性保持,但精神抑制的副作用明显增加。5)哌嗪2、5位被甲基取代时活性降低。
3、优选7个镇痛活性优良的化合物进行了急性毒性研究,结果有三个化合物的LD50大于2000 mg/kg,小鼠没有出现明显不良反应,为高度安全的化合物;有三个化合物的LD50大于477 mg/kg,但与其相应的药效学剂量(10、20及40 mg/kg)相比,仍具有较好的安全性。
4、优选了6个镇痛活性优良、副作用较小的化合物进行量效关系研究,研究表明:5个化合物的剂量效应曲线为经典的直方双曲线型,一个化合物的剂量效应曲线为倒U型曲线。其中4个化合物的镇痛效价4倍以上于阿斯匹林。
5、优选4个化合物采用大鼠纳络酮催促戒断试验进行初步成瘾性研究,初步判断此类化合物无明显成瘾性。
6、对优选化合物WG050406-1进行Biege犬初步药代动力学研究,研究表明采用灌胃单次给药250 mg,测得T1/2=0.5-0.9 h,Tmax=1.0 h,Cmax=1000-1200 ng/h,AUC(0-t)=2052 ng h/L,说明此化合物易于吸收,也易于代谢消除。
7、建立了芳烷哌嗪类衍生物的化合物库和基于APPRR193药效团叠合的3D-QSAR模型,经验证,该模型不仅能够很好解释实验结果,而且具有较准确的镇痛活性预测能力。
Pain is a complex problem with staggering negative health and economic consequences. Non-opioid analgesics are illustrative of the most active fields of research and hopefully represent some of the more promising strategies for discovering more effective and safer pain medications to meet the challenges of the future. For discoverying new analgesic candidates with exclusively intellectual property, in this thesis a series of arylpiperazines with analgesic activity were successfully designed, synthesized and screened on animal models, then the structure-potency relationships were investigated; Furthermore, the toxicity, dose-effect relationship, and addiction as well as pharmacokinetics of the candidates were also studied intensitively.
1. Several series of novel arylpiprazines were specifically designed and synthesized. The synthetic processes were fully investigated and optimized technical conditions have also been developed.Sixty-two new compounds were synthesized, and fifty-one of them were reported for the first time and the other nine ones only have CAS number without any detailed description. The structures of these compounds were characterized by NMR and MS.
2. The compounds were screened with the in vivo anti-pain agents screening models including hot-plate test and acetic acid-induced abdominal writhing test and found twenty compounds displaying remarkable analgesic activity. The structure-activity relationship (SAR) was demonstrated according to the results obtained: (1) phenyl piperazine acetylbenzene derivative compounds presented dramatic pain-relieving potency,i.e. the potency increased while an electron-donating group was introduced into aromatic ring,In contrast,the potency decreased while an electron-withdrawing group was grafted into aromatic ring. (2) The potency of these compounds declined when phenyl was replaced with other heteroaryl groups; (3) The potency was retained if a carbon atom was added between phenyl and piperazine, but sedative activity was enhanced; (4) The potency significantly lowered if carbonyl was oximated; (5) The potency also reduced if 2, 5 positions of piperazine were substituted by methyl group.
3. Seven compounds displaying remarkable analgesic potency were selected for the acute toxicity evaluation. The LD50 values of three of them exceeded 2000mg/kg, and no side-effects were observed, so they were considered extremely safe. The LD50 determination of the other three ones were more than 477mg/kg and also can be viewed as safe agent compared with its pharmacodynamics dose (10, 20, 40mg/kg).
4.Based on the above screening and evaluating system, six compounds with lower side-effect and potent antinociceptive activity were subjected to the next dose-effect relationship study.The results indicated five of them showed a hyperbolic curve, while one exhibited an inverted U-shaped dose response curve.And four compounds have pain-relieving potency four times superior to asipirin.
5. Naloxone withdrawal syndromes addictive researchs of the selected compounds were demostrated on mice.The results showed that these compounds possessed no addictive effect.
6. The optimized compounds exhibiting the best activity were chosen for pharmacokinetics study on beagles.The data revealed T1/2 is 0.5-0.9 h, Tmax is 1.0 h,Cmax is 1000-1200ng/L,AUC(0-t) is 2052ng h/L through intragastric administration,
7. Finally, 3D-QSAR model based on APPRR193 pharmacophore alignment was built to analyze these compounds, the predicted power of model was validated by arylpiperazines focused virtual library and further compound design.
1、定向设计5个系列芳烷哌嗪衍生物,对设计的化合物进行了合成研究工作,优化了合成线路与工艺。共设计合成6类化合物,合成了62个化合物,其中51个化合物未见文献报道,9个化合物虽有CAS号,但无性状描述。所得化合物结构经核磁共振、质谱确证。
2、建立动物镇痛药物筛选模型-热板法与扭体法,用此模型对合成的62个化合物进行镇痛活性的筛选,筛选结果表明有20个化合物有显著的镇痛活性。根据筛选结果,发现并总结了芳烷哌嗪类化合物的结构与镇痛活性的关系:1)苯基哌嗪苯乙酮类化合物具有良好镇痛活性,苯基上有供电子基取代时活性增强,吸电子取代基降低活性;2)苯基被其它杂芳基取代时活性降低;3)苯基与哌嗪之间增加一个碳原子活性保持,但镇静作用增加;苯基上供电子基团取代有利于活性增加,吸电子基团取代活性降低甚至消失;4)羰基肟化时活性显著降低;羰基被亚甲基取代时活性保持,但精神抑制的副作用明显增加。5)哌嗪2、5位被甲基取代时活性降低。
3、优选7个镇痛活性优良的化合物进行了急性毒性研究,结果有三个化合物的LD50大于2000 mg/kg,小鼠没有出现明显不良反应,为高度安全的化合物;有三个化合物的LD50大于477 mg/kg,但与其相应的药效学剂量(10、20及40 mg/kg)相比,仍具有较好的安全性。
4、优选了6个镇痛活性优良、副作用较小的化合物进行量效关系研究,研究表明:5个化合物的剂量效应曲线为经典的直方双曲线型,一个化合物的剂量效应曲线为倒U型曲线。其中4个化合物的镇痛效价4倍以上于阿斯匹林。
5、优选4个化合物采用大鼠纳络酮催促戒断试验进行初步成瘾性研究,初步判断此类化合物无明显成瘾性。
6、对优选化合物WG050406-1进行Biege犬初步药代动力学研究,研究表明采用灌胃单次给药250 mg,测得T1/2=0.5-0.9 h,Tmax=1.0 h,Cmax=1000-1200 ng/h,AUC(0-t)=2052 ng h/L,说明此化合物易于吸收,也易于代谢消除。
7、建立了芳烷哌嗪类衍生物的化合物库和基于APPRR193药效团叠合的3D-QSAR模型,经验证,该模型不仅能够很好解释实验结果,而且具有较准确的镇痛活性预测能力。
Pain is a complex problem with staggering negative health and economic consequences. Non-opioid analgesics are illustrative of the most active fields of research and hopefully represent some of the more promising strategies for discovering more effective and safer pain medications to meet the challenges of the future. For discoverying new analgesic candidates with exclusively intellectual property, in this thesis a series of arylpiperazines with analgesic activity were successfully designed, synthesized and screened on animal models, then the structure-potency relationships were investigated; Furthermore, the toxicity, dose-effect relationship, and addiction as well as pharmacokinetics of the candidates were also studied intensitively.
1. Several series of novel arylpiprazines were specifically designed and synthesized. The synthetic processes were fully investigated and optimized technical conditions have also been developed.Sixty-two new compounds were synthesized, and fifty-one of them were reported for the first time and the other nine ones only have CAS number without any detailed description. The structures of these compounds were characterized by NMR and MS.
2. The compounds were screened with the in vivo anti-pain agents screening models including hot-plate test and acetic acid-induced abdominal writhing test and found twenty compounds displaying remarkable analgesic activity. The structure-activity relationship (SAR) was demonstrated according to the results obtained: (1) phenyl piperazine acetylbenzene derivative compounds presented dramatic pain-relieving potency,i.e. the potency increased while an electron-donating group was introduced into aromatic ring,In contrast,the potency decreased while an electron-withdrawing group was grafted into aromatic ring. (2) The potency of these compounds declined when phenyl was replaced with other heteroaryl groups; (3) The potency was retained if a carbon atom was added between phenyl and piperazine, but sedative activity was enhanced; (4) The potency significantly lowered if carbonyl was oximated; (5) The potency also reduced if 2, 5 positions of piperazine were substituted by methyl group.
3. Seven compounds displaying remarkable analgesic potency were selected for the acute toxicity evaluation. The LD50 values of three of them exceeded 2000mg/kg, and no side-effects were observed, so they were considered extremely safe. The LD50 determination of the other three ones were more than 477mg/kg and also can be viewed as safe agent compared with its pharmacodynamics dose (10, 20, 40mg/kg).
4.Based on the above screening and evaluating system, six compounds with lower side-effect and potent antinociceptive activity were subjected to the next dose-effect relationship study.The results indicated five of them showed a hyperbolic curve, while one exhibited an inverted U-shaped dose response curve.And four compounds have pain-relieving potency four times superior to asipirin.
5. Naloxone withdrawal syndromes addictive researchs of the selected compounds were demostrated on mice.The results showed that these compounds possessed no addictive effect.
6. The optimized compounds exhibiting the best activity were chosen for pharmacokinetics study on beagles.The data revealed T1/2 is 0.5-0.9 h, Tmax is 1.0 h,Cmax is 1000-1200ng/L,AUC(0-t) is 2052ng h/L through intragastric administration,
7. Finally, 3D-QSAR model based on APPRR193 pharmacophore alignment was built to analyze these compounds, the predicted power of model was validated by arylpiperazines focused virtual library and further compound design.
引文
[1] DeLeo J. A. Basic science of pain. The Journal of Bone and Joint Surgery,2006, 88 (Suppl 2):58-62
[2] McBeth J., Jones K. Epidemiology of chronic musculoskeletal pain. Best Practice & Research Clinical Rheumatology,2007, 21: 403-425
[3] Driessen B., Zarucco L. Pain: From Diagnosis to Effective Treatment. Clinical Techniques in Equine Practice,2007, 6:126-134
[4] Pruimboom L., van Dam A. C. Chronic pain: a non-use disease. Medical Hypotheses,2007, 68:506-511
[5] Farsi M., Gitto L. A statistical analysis of pain relief after surgical operations. Health Policy,2007, 83:382-390
[6] Cepeda M. S., Farrar J. T. Economic Evaluation of Oral Treatments for Neuropathic Pain. The Journal of Pain,2006, 7:119-128
[7]姚尚龙,杨磊疼痛治疗学进展.华中医学杂志,2007,31(2):73-74
[8]胡书明.止痛是治标不治本吗?.癌症康复,2004,2:7-7
[9]陈军.疼痛控制和研究的十年.神经解剖学杂志,2001,4(2):308-308
[10]赵英.疼痛问题的现状.中国社区医师, 2006, 22(14):7-7
[11] McCracken L. M., Hoskins J., Eccleston C. Concerns About Medication and Medication Use in Chronic Pain. The Journal of Pain,2006, 7:726-734
[12] Buvanendran A., Reuben S. S., Kroin J. S. Recent advances in nonopioid analgesics for acute pain management. Techniques in Regional Anesthesia and Pain Management,2007, 11:19-26
[13] Faerber L., Drechsler S., Ladenburger S., et al. The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation. European Journal of Pharmacology, 2007, 560:1-8
[14] Diaz G., Flood P. Strategies for effective postoperative pain management. Minerva Anestesiologica,2006, 72:145-150
[15] Bingham S., Beswick P. J., Blum D. E., et al. The role of the cylooxygenase pathway in nociception and pain. Seminars in Cell & Developmental Biology, 2006, 17:544-554
[16] Pleuvry B. J. Opioid mechanisms and opioid drugs. Anaesthesia & intensive care medicine,2005, 6:30-34
[17] Forde G. Adjuvant analgesics for the treatment of neuropathic pain: evaluating efficacy and safety profiles.The Journal of Family Practice,2007, 56:3-12
[18] Gutierrez-Alvarez A. M., Beltran-Rodriguez J., Moreno C. B. Antiepileptic Drugs in Treatment of Pain Caused by Diabetic Neuropathy. Journal of Pain and Symptom Management,2007, 34:201-208
[19] Mattia C., Coluzzi F. Antidepressants in chronic neuropathic pain. Mini Reviews in Medicinal Chemistry,2003, 3:773-784
[20] White P. F. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesthesia&Analgesia,2005, 101: 5-22
[21] Kis B., Snipes J. A., Busija D. W. Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. The Journal of Pharmacology and Experimental Therapeutics,2005, 315:1-7
[22] Laine L. GI risk and risk factors of NSAIDs. Journal of Cardiovascular Pharmacology,2006, 47 (Suppl 1):60-66
[23] Mehlisch D. R., Ardia A., Pallotta T. Analgesia with ibuprofen arginate versus conventional ibuprofen for patients with dysmenorrhea: a crossover trial. Current Therapeutic Research,2003, 64:327-337
[24] Yamazaki T., Muramoto M. Oe T., Morikawa N., et al. Diclofenac, a non-steroidal anti-inflammatory drug, suppresses apoptosis induced by endoplasmic reticulum stresses by inhibiting caspase signaling. Neuropharmacology,2006, 50:558-567
[25] Ladner E., Plattner R., Friesenecker B., et al. Non-opioid analgesics-irreplaceable in cancer pain therapy Anasthesiol Intensivmed Notfallmed Schmerzther,2000, 35:677-84
[26] Hutchison R. COX-2-selective NSAIDs. American Journal of Nursing,2004, 104:52-55
[27] Freedman B. M., Balakrishnan T. P., O'Hara E. L. Celecoxib reduces narcotic use and pain following augmentation mammaplasty. Aesthetic Surgery Journal, 2006, 26:24-28
[28] Naef M., Curatolo M., Petersen-Felix S., et al. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain,2003, 105:79-88
[29] Kalso E. Oxycodone. Journal of Pain and Symptom Management,2005, 29: 47-56
[30] Ho K.-Y., Gan T. J., Habib A. S. Gabapentin and postoperative pain - a systematic review of randomized controlled trials. Pain,2006, 126: 91-101
[31] Kennedy J. D. Neuropathic pain: molecular complexity underlies continuing unmet medical need. Journal of Medicinal Chemistry,2007, 50:2547-2556
[32] Rogers M., Tang L., Madge D. J., Stevens E. B. The role of sodium channels in neuropathic pain. Seminars in Cell & Developmental Biology,2006, 17:571-581
[33] Wernicke J. F., Raskin J., Rosen A., et al. Duloxetine in the long-term management of diabetic peripheral neuropathic pain: An open-label, 52-week extension of a randomized controlled clinical trial. Current Therapeutic Research,2006, 67:283-304
[34] Volkow N. D., Wang G.-J., Fowler J. S., et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biological Psychiatry,2005, 57:640-646
[35] Alfinito P. D., Huselton C., Chen X., et al. C. Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats. Brain Research,2006, 1098:71-78
[36] Immke D. C., Gavva N. R. The TRPV1 receptor and nociception. Seminars in Cell & Developmental Biology,2006, 17:582-591
[37] Javan M., Kazemi B., Ahmadiani A., et al. Dexamethasone mimics the inhibitory effect of chronic pain on the development of tolerance to morphine analgesia and compensates for morphine induced changes in G proteins gene expression. Brain Research,2006, 1104:73-79
[38] Dahlof C., Sawyer J. P. 2-21-05 Zolmitriptan (`Zomig'): Consistent pain relief over multiple migraine attacks following initial treatment, and for recurrence of a migraine attack. Journal of the Neurological Sciences,1997, 150:103-104
[39] Filitz J., Ihmsen H., Gunther W., et al. Supra-additive effects of tramadol and acetaminophen in a human pain model. Pain In Press, Corrected Proof
[40] Lynch M. E., Clark A. J., Sawynok J., et al. Topical Amitriptyline and Ketamine in Neuropathic Pain Syndromes: An Open-Label Study. The Journal of Pain,2005, 6:644-649
[41] Okuse K. Pain signalling pathways: From cytokines to ion channels. The International Journal of Biochemistry & Cell Biology,2007, 39:490-496
[42] Almeida T. F., Roizenblatt S., Tufik S. Afferent pain pathways: a neuroanatomical review. Brain Research,2004, 1000:40-56
[43] Goffaux P., Redmond W. J., Rainville P., et al. Descending analgesia - When the spine echoes what the brain expects. Pain,2007, 130:137-143
[44] Almeida A., Leite-Almeida H., Tavares I. Medullary control of nociceptive transmission: Reciprocal dual communication with the spinal cord. Drug Discovery Today: Disease Mechanisms,2006, 3:305-312
[45] Khan A. A., Iadarola M., Yang H.-Y. T., et al. Expression of COX-1 and COX-2 in a Clinical Model of Acute Inflammation. The Journal of Pain,2007, 8:349-354
[46] Markman J. D., Dworkin R. H. Ion channel targets and treatment efficacy in neuropathic pain. The Journal of Pain ,2006, 7:38-47
[47] May L. T., Christopoulos A. Allosteric modulators of G-protein-coupled receptors. Current Opinion in Pharmacology,2003, 3:551-556
[48] Childers W. E. Jr., Baudy R. B. N-methyl-D-aspartate antagonists and neuropathic pain: the search for relief. Journal of Medicinal Chemistry,2007, 50:2557-2562
[49] Morales-Alcelay S., Rubio L., Martinez A. AMPA glutamate receptors and neuropathic pain. Mini Reviews in Medicinal Chemistry,2003, 3:757-763
[50] Schkeryantz J. M., Kingston A. E., Johnson M. P. Prospects for metabotropic glutamate 1 receptor antagonists in the treatment of neuropathic pain. Journal of Medicinal Chemistry,2007, 50:2563-8
[51] Bleakman D., Alt A., Nisenbaum, E. S. Glutamate receptors and pain. Seminars in Cell and Developmental Biology,2006, 17:592-604
[52] Brandt M. R., Cummons T. A., Potestio L., et al. Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity. The Journal of Pharmacology and Experimental Therapeutics,2005, 313: 1379-1386
[53] Chaudhari M., Chaudhari S., Mather S. Ketamine for pain relief in acute pancreatitis. Acute Pain,2007, 9:83-86
[54] Prakash C., Cui D., Potchoiba M. J., Butler T. Metabolism, distribution and excretion of a selective N-methyl-D-aspartate receptor antagonist, traxoprodil, in rats and dogs. Drug Metabolism and Disposition,2007, 35:1350-1364
[55] Triggle D. J. Calcium channel antagonists: Clinical uses-Past, present and future. Biochemical Pharmacology,2007, 74:1-9
[56] Gribkoff V. K. The role of voltage-gated calcium channels in pain and nociception. Seminars in Cell & Developmental Biology,2006, 17:555-564
[57] Smith M. T., Cabot P. J., Ross F. B., et al. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain,2002, 96:119-127
[58] Field M. J., Li Z., Schwarz J. B. Ca2+ channel alpha2-delta ligands for the treatment of neuropathic pain. Journal of Medicinal Chemistry,2007, 50:2569-2575
[59] Takahashi Y., Hashimoto K., Tsuji S. Successful use of zonisamide for central poststroke pain. The Journal of Pain,2004, 5:192-194
[60] Ocana M., Cendan C. M., Cobos E. J., et al. Potassium channels and pain: present realities and future opportunities. European Journal of Pharmacology,2004, 500:203-219
[61] Munro G., Dalby-Brown W. Kv7 (KCNQ) channel modulators and neuropathic pain. Journal of Medicinal Chemistry,2007, 50:2576-82
[62] Porter R. J., Nohria V., Rundfeldt C. Retigabine. Neurotherapeutics,2007, 4:149-154
[63] Kobal G., Hummel T., Friedmann T., et al. Dose-related effects of flupirtine on the pain-related evoked potential. Pain,1990, 41:201
[64] Devor M. Sodium Channels and Mechanisms of Neuropathic Pain. The Journal of Pain,2006, 7: 3-12
[65] Lindia J. A., Kohler M. G., Martin W. J., et al. Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats. Pain,2005, 117:145-153
[66] Hoyt S. B., London C., Gorin D., et al. Discovery of a novel class of benzazepinone Nav1.7 blockers: Potential treatments for neuropathic pain. Bioorganic & Medicinal Chemistry Letters,2007, 17:4630-4634
[67] Dong X. W., Goregoaker S., Engler H., et al. Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience,2007, 146:812-821
[68] Padilla F., Couble M.-L., Coste B., et al. Expression and localization of the Nav1.9 sodium channel in enteric neurons and in trigeminal sensory endings: Implication for intestinal reflex function and orofacial pain. Molecular and Cellular Neuroscience,2007, 35:138-152
[69] Dick I. E., Brochu R. M., Purohit Y., et al. Sodium Channel Blockade May Contribute to the Analgesic Efficacy of Antidepressants. The Journal of Pain,2007, 8:315-324
[70] Mico J. A., Ardid D., Berrocoso E., Eschalier A. Antidepressants and pain. Trends in Pharmacological Sciences,2006, 27:348-354
[71] Szallasi A., Cortright D. N., Blum C. A., et al. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nature Reviews Drug Discovery,2007, 6,:357-372
[72] Rami H. K., Thompson M., Stemp G., et al. Discovery of SB-705498: A potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorganic & Medicinal Chemistry Letters,2006, 16:3287-3291
[73] Cui M., Honore P., Zhong C., et al. TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. The Journal of Neuroscience,2006, 26:9385-93.
[74] Jancso G., Santha P., Oszlacs O., Nyari T. 383 Perineural capsaicin and resiniferatoxin induce selective regional analgesia and phenotypic switch of primary sensory neurons expressing TRPV1. European Journal of Pain,2007, 11:170
[75] Neubert J. Modulating effects of resiniferatoxin on orofacial pain. The Journal of Pain,2007, 8:20
[76] Vaughan C. W. Stressed-out endogenous cannabinoids relieve pain. Trends in Pharmacological Sciences,2006, 27:69-71
[77] Svendsen K. B., Jensen T. S., Bach F. W. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. The British Medical Journal,2004, 329:253
[78] Grant I., Cahn B. R. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Clinical Neuroscience Research,2005, 5:185-199
[79] Giblin G. M., O'Shaughnessy C. T., Naylor A., et al. Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-4- (trifluoromethyl)-5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain. Journal of Medicinal Chemistry,2007, 50:2597-2600
[80] Decker M. W., Rueter L. E., Bitner R. S. Nicotinic acetylcholine receptor agonists: a potential new class of analgesics. Current Topics in Medicinal Chemistry,2004, 4:369-384
[81] Wilens T. E., Verlinden M. H., Adler L. A., et al. ABT-089, A Neuronal Nicotinic Receptor Partial Agonist, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Pilot Study. Biological Psychiatry,2006, 59:1065-1070
[82] Geerts H. Indicators of neuroprotection with galantamine. Brain ResearchBulletin,2005, 64:519-524
[83] Zhang X.F., McKenna D. G., Briggs C. A. Epibatidine, a nicotinic acetylcholine receptor agonist, inhibits the capsaicin response in dorsal root ganglion neurons. Brain Research,2001, 919:166-168
[84] Ghosh S., Nie A., An J., Huang Z. Structure-based virtual screening of chemical libraries for drug discovery. Current Opinion in Chemical Biology,2006, 10:194-202
[85] Bacilieri M., Moro S. Ligand-based drug design methodologies in drug discovery process: an overview. Current Drug Discovery Technologies,2006, 3:155-65
[86] Akamatsu M. Current state and perspectives of 3D-QSAR. Current Topics in Medicinal Chemistry,2002, 2:1381-1394
[87] Dudek A. Z., Arodz T., Galvez J. Computational methods in developing quantitative structure-activity relationships (QSAR): a review. Combinatorial Chemistry&High Throughput Screening,2006, 9:213-28
[88] Evans D. A., Doman T. N., Thorner D. A., et al. 3D QSAR methods: Phase and Catalyst compared. Journal of Chemical Information and Modeling,2007, 47:1248-57
[89] Ayajiki K., Okamura T., Toda N. Flunarizine, an anti-migraine agent, impairs nitroxidergic nerve function in cerebral arteries. European Journal of Pharmacology,1997, 329:49-53
[90] Toriu N., Akaike A., Yasuyoshi H., et al. Lomerizine, a Ca2+Channel Blocker, Reduces Glutamate-induced Neurotoxicity and Ischemia/Reperfusion Damage in Rat Retina. Experimental Eye Research:2000, 70:475-484
[91] Jones E. B., Gonzalez E. R., Boggs J. G., et al. Safety and Efficacy of Rectal Prochlorperazine for the Treatment of Migraine in the Emergency Department. Annals of Emergency Medicine,1994, 24:237-241
[92] El-Shafie F. S., Omar A., et al. Synthesis and Analgesic Activity of New 1-(p-Substituted phenacyl)-4-substituted Piperazines and Piperidines and Their Carbinol Derivatives. Scientia Pharmaceutica,1994, 62:389-403
[93] Vicente Gómez-Parra F. S., César Yagüe. Syntheses of 1-Aryl-2- {4-[4- (3-oxobutyl) phenyl]piperazin-1-yl}ethanones. Archiv der Pharmazie,1986, 319:552-558
[94] Yu X. M., Hoheisel U., Mense S. Effects of a novel piperazine derivative (CGP 29030A) on nociceptive dorsal horn neurons in the rat. Drugs Under Experimental and Clinical Research,1992, 18:447-59
[95] Shimokawa N., Nakamura H., Shimakawa K., et al. Studies on analgesic agents. 1.Preparation of 1,2-diphenyl-2-(4-substituted 1-piperazinyl)ethanol derivatives and structure-activity relationships. Journal of Medicinal Chemistry,1979, 22:58-63
[96] Valenzano K. J., Grant E. R., Wu G., et al. N-(4-tertiarybutylphenyl)-4- (3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. in vitro characterization and pharmacokinetic properties. The Journal of Pharmacology and Experimental Therapeutics,2003, 306:377-86
[97] Westaway S. M. The potential of transient receptor potential vanilloid type 1 channel modulators for the treatment of pain. Journal of Medicinal Chemistry,2007, 50:2589-96
[98] Vejdelek Z. B., Vaclav B, Svatek, et al. Synthesis of Several Compounds Related to 1-(4-Methylsulfonylphenacyl)-4-phenylpiperazine and their pharmacological Screening. Collection of Czechoslovak Chemical Communications,1985, 50:1498-1506
[99] Gannon R. L., Millan M. J. Serotonin1A autoreceptor activation by S 15535 enhances circadian activity rhythms in hamsters: evaluation of potential interactions with serotonin2A and serotonin2C receptors. Neuroscience,2006, 137:287-299
[100] Fuller R. W., Snoddy H. D., Molloy B. B. Central serotonin agonist actions of LY 165163, 1-(m-trifluoromethylphenyl)-4-(p-aminophenylethyl) piperazine, in rats. The Journal of Pharmacology and Experimental Therapeutics,1986, 239:454-459
[101] Glennon R. A., Yousif M. Y., Ismaiel A. M., et al. Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands. Journal of Medicinal Chemistry,1991, 34:3360-3365
[102] Shiah I. S., Lin C.L, Mao C, et al. Ziprasidone in the treatment of Parkinson's disease psychosis. European Psychiatry,2006, 21:578-579
[103] Grisar J Martin, Claxton George P . 2-Hydroxy-5-(1-hydroxy-2- piperazinylethyl)-benzoicacid derivatives.US4255575,1981
[104] Kikumoto Ryoji F.H.,Nakao Kentchiro,Sugano Mamoru. Alkylenedioxybenzene and acid addition salts thereof useful as hypotensives. US4684651,1987
[105] Isaacson Scott A, Dampuam Alexander Y. Isolating multiple authentication channels, each using multiple authentication models.US200261895,2005
[106]苏冰,王雅丽. 1-(2-甲氧基苯基)哌嗪的合成改进.中国现代应用药学1999, 16(6):33-34
[107]吴义杰,周廷森. N-[4-[4-(4-甲氧基苯基)-1-哌嗪基]苯基]氨基甲酰肼的合成.中国医药工业杂志,1995, 29(9):415-416
[108] Lyon R. A., Titeler M., McKenney J. D., et al. Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergic agents. Journal of Medicinal Chemistry,1986, 29:630-634
[109]闫丽,董国君. 2-氯代苯并噻唑的合成研究.应用科技,2002, 29(9):65-66
[110] Li Jianqi , Hang. Liying, Zhang Chunnian, et al. Aralkyl-ketone piperazine derivatives and their uses as new antalgic or ataractic agent. CN1150176C,2004
[111] Marinho B. G., Miranda L. S., Gomes N. M., et al. Antinociceptive action of (+/-)-cis-(6-ethyl-tetrahydropyran-2-yl)-formic acid in mice. European Journal of Pharmacology,2006, 550:47-53
[112] Amresh G., Singh P. N., Rao Ch, Antinociceptive and antiarthritic activity of Cissampelos pareira roots. Journal of Ethnopharmacology,2007, 111:531-536
[2] McBeth J., Jones K. Epidemiology of chronic musculoskeletal pain. Best Practice & Research Clinical Rheumatology,2007, 21: 403-425
[3] Driessen B., Zarucco L. Pain: From Diagnosis to Effective Treatment. Clinical Techniques in Equine Practice,2007, 6:126-134
[4] Pruimboom L., van Dam A. C. Chronic pain: a non-use disease. Medical Hypotheses,2007, 68:506-511
[5] Farsi M., Gitto L. A statistical analysis of pain relief after surgical operations. Health Policy,2007, 83:382-390
[6] Cepeda M. S., Farrar J. T. Economic Evaluation of Oral Treatments for Neuropathic Pain. The Journal of Pain,2006, 7:119-128
[7]姚尚龙,杨磊疼痛治疗学进展.华中医学杂志,2007,31(2):73-74
[8]胡书明.止痛是治标不治本吗?.癌症康复,2004,2:7-7
[9]陈军.疼痛控制和研究的十年.神经解剖学杂志,2001,4(2):308-308
[10]赵英.疼痛问题的现状.中国社区医师, 2006, 22(14):7-7
[11] McCracken L. M., Hoskins J., Eccleston C. Concerns About Medication and Medication Use in Chronic Pain. The Journal of Pain,2006, 7:726-734
[12] Buvanendran A., Reuben S. S., Kroin J. S. Recent advances in nonopioid analgesics for acute pain management. Techniques in Regional Anesthesia and Pain Management,2007, 11:19-26
[13] Faerber L., Drechsler S., Ladenburger S., et al. The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation. European Journal of Pharmacology, 2007, 560:1-8
[14] Diaz G., Flood P. Strategies for effective postoperative pain management. Minerva Anestesiologica,2006, 72:145-150
[15] Bingham S., Beswick P. J., Blum D. E., et al. The role of the cylooxygenase pathway in nociception and pain. Seminars in Cell & Developmental Biology, 2006, 17:544-554
[16] Pleuvry B. J. Opioid mechanisms and opioid drugs. Anaesthesia & intensive care medicine,2005, 6:30-34
[17] Forde G. Adjuvant analgesics for the treatment of neuropathic pain: evaluating efficacy and safety profiles.The Journal of Family Practice,2007, 56:3-12
[18] Gutierrez-Alvarez A. M., Beltran-Rodriguez J., Moreno C. B. Antiepileptic Drugs in Treatment of Pain Caused by Diabetic Neuropathy. Journal of Pain and Symptom Management,2007, 34:201-208
[19] Mattia C., Coluzzi F. Antidepressants in chronic neuropathic pain. Mini Reviews in Medicinal Chemistry,2003, 3:773-784
[20] White P. F. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesthesia&Analgesia,2005, 101: 5-22
[21] Kis B., Snipes J. A., Busija D. W. Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. The Journal of Pharmacology and Experimental Therapeutics,2005, 315:1-7
[22] Laine L. GI risk and risk factors of NSAIDs. Journal of Cardiovascular Pharmacology,2006, 47 (Suppl 1):60-66
[23] Mehlisch D. R., Ardia A., Pallotta T. Analgesia with ibuprofen arginate versus conventional ibuprofen for patients with dysmenorrhea: a crossover trial. Current Therapeutic Research,2003, 64:327-337
[24] Yamazaki T., Muramoto M. Oe T., Morikawa N., et al. Diclofenac, a non-steroidal anti-inflammatory drug, suppresses apoptosis induced by endoplasmic reticulum stresses by inhibiting caspase signaling. Neuropharmacology,2006, 50:558-567
[25] Ladner E., Plattner R., Friesenecker B., et al. Non-opioid analgesics-irreplaceable in cancer pain therapy Anasthesiol Intensivmed Notfallmed Schmerzther,2000, 35:677-84
[26] Hutchison R. COX-2-selective NSAIDs. American Journal of Nursing,2004, 104:52-55
[27] Freedman B. M., Balakrishnan T. P., O'Hara E. L. Celecoxib reduces narcotic use and pain following augmentation mammaplasty. Aesthetic Surgery Journal, 2006, 26:24-28
[28] Naef M., Curatolo M., Petersen-Felix S., et al. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain,2003, 105:79-88
[29] Kalso E. Oxycodone. Journal of Pain and Symptom Management,2005, 29: 47-56
[30] Ho K.-Y., Gan T. J., Habib A. S. Gabapentin and postoperative pain - a systematic review of randomized controlled trials. Pain,2006, 126: 91-101
[31] Kennedy J. D. Neuropathic pain: molecular complexity underlies continuing unmet medical need. Journal of Medicinal Chemistry,2007, 50:2547-2556
[32] Rogers M., Tang L., Madge D. J., Stevens E. B. The role of sodium channels in neuropathic pain. Seminars in Cell & Developmental Biology,2006, 17:571-581
[33] Wernicke J. F., Raskin J., Rosen A., et al. Duloxetine in the long-term management of diabetic peripheral neuropathic pain: An open-label, 52-week extension of a randomized controlled clinical trial. Current Therapeutic Research,2006, 67:283-304
[34] Volkow N. D., Wang G.-J., Fowler J. S., et al. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biological Psychiatry,2005, 57:640-646
[35] Alfinito P. D., Huselton C., Chen X., et al. C. Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats. Brain Research,2006, 1098:71-78
[36] Immke D. C., Gavva N. R. The TRPV1 receptor and nociception. Seminars in Cell & Developmental Biology,2006, 17:582-591
[37] Javan M., Kazemi B., Ahmadiani A., et al. Dexamethasone mimics the inhibitory effect of chronic pain on the development of tolerance to morphine analgesia and compensates for morphine induced changes in G proteins gene expression. Brain Research,2006, 1104:73-79
[38] Dahlof C., Sawyer J. P. 2-21-05 Zolmitriptan (`Zomig'): Consistent pain relief over multiple migraine attacks following initial treatment, and for recurrence of a migraine attack. Journal of the Neurological Sciences,1997, 150:103-104
[39] Filitz J., Ihmsen H., Gunther W., et al. Supra-additive effects of tramadol and acetaminophen in a human pain model. Pain In Press, Corrected Proof
[40] Lynch M. E., Clark A. J., Sawynok J., et al. Topical Amitriptyline and Ketamine in Neuropathic Pain Syndromes: An Open-Label Study. The Journal of Pain,2005, 6:644-649
[41] Okuse K. Pain signalling pathways: From cytokines to ion channels. The International Journal of Biochemistry & Cell Biology,2007, 39:490-496
[42] Almeida T. F., Roizenblatt S., Tufik S. Afferent pain pathways: a neuroanatomical review. Brain Research,2004, 1000:40-56
[43] Goffaux P., Redmond W. J., Rainville P., et al. Descending analgesia - When the spine echoes what the brain expects. Pain,2007, 130:137-143
[44] Almeida A., Leite-Almeida H., Tavares I. Medullary control of nociceptive transmission: Reciprocal dual communication with the spinal cord. Drug Discovery Today: Disease Mechanisms,2006, 3:305-312
[45] Khan A. A., Iadarola M., Yang H.-Y. T., et al. Expression of COX-1 and COX-2 in a Clinical Model of Acute Inflammation. The Journal of Pain,2007, 8:349-354
[46] Markman J. D., Dworkin R. H. Ion channel targets and treatment efficacy in neuropathic pain. The Journal of Pain ,2006, 7:38-47
[47] May L. T., Christopoulos A. Allosteric modulators of G-protein-coupled receptors. Current Opinion in Pharmacology,2003, 3:551-556
[48] Childers W. E. Jr., Baudy R. B. N-methyl-D-aspartate antagonists and neuropathic pain: the search for relief. Journal of Medicinal Chemistry,2007, 50:2557-2562
[49] Morales-Alcelay S., Rubio L., Martinez A. AMPA glutamate receptors and neuropathic pain. Mini Reviews in Medicinal Chemistry,2003, 3:757-763
[50] Schkeryantz J. M., Kingston A. E., Johnson M. P. Prospects for metabotropic glutamate 1 receptor antagonists in the treatment of neuropathic pain. Journal of Medicinal Chemistry,2007, 50:2563-8
[51] Bleakman D., Alt A., Nisenbaum, E. S. Glutamate receptors and pain. Seminars in Cell and Developmental Biology,2006, 17:592-604
[52] Brandt M. R., Cummons T. A., Potestio L., et al. Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity. The Journal of Pharmacology and Experimental Therapeutics,2005, 313: 1379-1386
[53] Chaudhari M., Chaudhari S., Mather S. Ketamine for pain relief in acute pancreatitis. Acute Pain,2007, 9:83-86
[54] Prakash C., Cui D., Potchoiba M. J., Butler T. Metabolism, distribution and excretion of a selective N-methyl-D-aspartate receptor antagonist, traxoprodil, in rats and dogs. Drug Metabolism and Disposition,2007, 35:1350-1364
[55] Triggle D. J. Calcium channel antagonists: Clinical uses-Past, present and future. Biochemical Pharmacology,2007, 74:1-9
[56] Gribkoff V. K. The role of voltage-gated calcium channels in pain and nociception. Seminars in Cell & Developmental Biology,2006, 17:555-564
[57] Smith M. T., Cabot P. J., Ross F. B., et al. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain,2002, 96:119-127
[58] Field M. J., Li Z., Schwarz J. B. Ca2+ channel alpha2-delta ligands for the treatment of neuropathic pain. Journal of Medicinal Chemistry,2007, 50:2569-2575
[59] Takahashi Y., Hashimoto K., Tsuji S. Successful use of zonisamide for central poststroke pain. The Journal of Pain,2004, 5:192-194
[60] Ocana M., Cendan C. M., Cobos E. J., et al. Potassium channels and pain: present realities and future opportunities. European Journal of Pharmacology,2004, 500:203-219
[61] Munro G., Dalby-Brown W. Kv7 (KCNQ) channel modulators and neuropathic pain. Journal of Medicinal Chemistry,2007, 50:2576-82
[62] Porter R. J., Nohria V., Rundfeldt C. Retigabine. Neurotherapeutics,2007, 4:149-154
[63] Kobal G., Hummel T., Friedmann T., et al. Dose-related effects of flupirtine on the pain-related evoked potential. Pain,1990, 41:201
[64] Devor M. Sodium Channels and Mechanisms of Neuropathic Pain. The Journal of Pain,2006, 7: 3-12
[65] Lindia J. A., Kohler M. G., Martin W. J., et al. Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats. Pain,2005, 117:145-153
[66] Hoyt S. B., London C., Gorin D., et al. Discovery of a novel class of benzazepinone Nav1.7 blockers: Potential treatments for neuropathic pain. Bioorganic & Medicinal Chemistry Letters,2007, 17:4630-4634
[67] Dong X. W., Goregoaker S., Engler H., et al. Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience,2007, 146:812-821
[68] Padilla F., Couble M.-L., Coste B., et al. Expression and localization of the Nav1.9 sodium channel in enteric neurons and in trigeminal sensory endings: Implication for intestinal reflex function and orofacial pain. Molecular and Cellular Neuroscience,2007, 35:138-152
[69] Dick I. E., Brochu R. M., Purohit Y., et al. Sodium Channel Blockade May Contribute to the Analgesic Efficacy of Antidepressants. The Journal of Pain,2007, 8:315-324
[70] Mico J. A., Ardid D., Berrocoso E., Eschalier A. Antidepressants and pain. Trends in Pharmacological Sciences,2006, 27:348-354
[71] Szallasi A., Cortright D. N., Blum C. A., et al. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nature Reviews Drug Discovery,2007, 6,:357-372
[72] Rami H. K., Thompson M., Stemp G., et al. Discovery of SB-705498: A potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorganic & Medicinal Chemistry Letters,2006, 16:3287-3291
[73] Cui M., Honore P., Zhong C., et al. TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. The Journal of Neuroscience,2006, 26:9385-93.
[74] Jancso G., Santha P., Oszlacs O., Nyari T. 383 Perineural capsaicin and resiniferatoxin induce selective regional analgesia and phenotypic switch of primary sensory neurons expressing TRPV1. European Journal of Pain,2007, 11:170
[75] Neubert J. Modulating effects of resiniferatoxin on orofacial pain. The Journal of Pain,2007, 8:20
[76] Vaughan C. W. Stressed-out endogenous cannabinoids relieve pain. Trends in Pharmacological Sciences,2006, 27:69-71
[77] Svendsen K. B., Jensen T. S., Bach F. W. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. The British Medical Journal,2004, 329:253
[78] Grant I., Cahn B. R. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Clinical Neuroscience Research,2005, 5:185-199
[79] Giblin G. M., O'Shaughnessy C. T., Naylor A., et al. Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-4- (trifluoromethyl)-5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain. Journal of Medicinal Chemistry,2007, 50:2597-2600
[80] Decker M. W., Rueter L. E., Bitner R. S. Nicotinic acetylcholine receptor agonists: a potential new class of analgesics. Current Topics in Medicinal Chemistry,2004, 4:369-384
[81] Wilens T. E., Verlinden M. H., Adler L. A., et al. ABT-089, A Neuronal Nicotinic Receptor Partial Agonist, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Pilot Study. Biological Psychiatry,2006, 59:1065-1070
[82] Geerts H. Indicators of neuroprotection with galantamine. Brain ResearchBulletin,2005, 64:519-524
[83] Zhang X.F., McKenna D. G., Briggs C. A. Epibatidine, a nicotinic acetylcholine receptor agonist, inhibits the capsaicin response in dorsal root ganglion neurons. Brain Research,2001, 919:166-168
[84] Ghosh S., Nie A., An J., Huang Z. Structure-based virtual screening of chemical libraries for drug discovery. Current Opinion in Chemical Biology,2006, 10:194-202
[85] Bacilieri M., Moro S. Ligand-based drug design methodologies in drug discovery process: an overview. Current Drug Discovery Technologies,2006, 3:155-65
[86] Akamatsu M. Current state and perspectives of 3D-QSAR. Current Topics in Medicinal Chemistry,2002, 2:1381-1394
[87] Dudek A. Z., Arodz T., Galvez J. Computational methods in developing quantitative structure-activity relationships (QSAR): a review. Combinatorial Chemistry&High Throughput Screening,2006, 9:213-28
[88] Evans D. A., Doman T. N., Thorner D. A., et al. 3D QSAR methods: Phase and Catalyst compared. Journal of Chemical Information and Modeling,2007, 47:1248-57
[89] Ayajiki K., Okamura T., Toda N. Flunarizine, an anti-migraine agent, impairs nitroxidergic nerve function in cerebral arteries. European Journal of Pharmacology,1997, 329:49-53
[90] Toriu N., Akaike A., Yasuyoshi H., et al. Lomerizine, a Ca2+Channel Blocker, Reduces Glutamate-induced Neurotoxicity and Ischemia/Reperfusion Damage in Rat Retina. Experimental Eye Research:2000, 70:475-484
[91] Jones E. B., Gonzalez E. R., Boggs J. G., et al. Safety and Efficacy of Rectal Prochlorperazine for the Treatment of Migraine in the Emergency Department. Annals of Emergency Medicine,1994, 24:237-241
[92] El-Shafie F. S., Omar A., et al. Synthesis and Analgesic Activity of New 1-(p-Substituted phenacyl)-4-substituted Piperazines and Piperidines and Their Carbinol Derivatives. Scientia Pharmaceutica,1994, 62:389-403
[93] Vicente Gómez-Parra F. S., César Yagüe. Syntheses of 1-Aryl-2- {4-[4- (3-oxobutyl) phenyl]piperazin-1-yl}ethanones. Archiv der Pharmazie,1986, 319:552-558
[94] Yu X. M., Hoheisel U., Mense S. Effects of a novel piperazine derivative (CGP 29030A) on nociceptive dorsal horn neurons in the rat. Drugs Under Experimental and Clinical Research,1992, 18:447-59
[95] Shimokawa N., Nakamura H., Shimakawa K., et al. Studies on analgesic agents. 1.Preparation of 1,2-diphenyl-2-(4-substituted 1-piperazinyl)ethanol derivatives and structure-activity relationships. Journal of Medicinal Chemistry,1979, 22:58-63
[96] Valenzano K. J., Grant E. R., Wu G., et al. N-(4-tertiarybutylphenyl)-4- (3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. in vitro characterization and pharmacokinetic properties. The Journal of Pharmacology and Experimental Therapeutics,2003, 306:377-86
[97] Westaway S. M. The potential of transient receptor potential vanilloid type 1 channel modulators for the treatment of pain. Journal of Medicinal Chemistry,2007, 50:2589-96
[98] Vejdelek Z. B., Vaclav B, Svatek, et al. Synthesis of Several Compounds Related to 1-(4-Methylsulfonylphenacyl)-4-phenylpiperazine and their pharmacological Screening. Collection of Czechoslovak Chemical Communications,1985, 50:1498-1506
[99] Gannon R. L., Millan M. J. Serotonin1A autoreceptor activation by S 15535 enhances circadian activity rhythms in hamsters: evaluation of potential interactions with serotonin2A and serotonin2C receptors. Neuroscience,2006, 137:287-299
[100] Fuller R. W., Snoddy H. D., Molloy B. B. Central serotonin agonist actions of LY 165163, 1-(m-trifluoromethylphenyl)-4-(p-aminophenylethyl) piperazine, in rats. The Journal of Pharmacology and Experimental Therapeutics,1986, 239:454-459
[101] Glennon R. A., Yousif M. Y., Ismaiel A. M., et al. Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands. Journal of Medicinal Chemistry,1991, 34:3360-3365
[102] Shiah I. S., Lin C.L, Mao C, et al. Ziprasidone in the treatment of Parkinson's disease psychosis. European Psychiatry,2006, 21:578-579
[103] Grisar J Martin, Claxton George P . 2-Hydroxy-5-(1-hydroxy-2- piperazinylethyl)-benzoicacid derivatives.US4255575,1981
[104] Kikumoto Ryoji F.H.,Nakao Kentchiro,Sugano Mamoru. Alkylenedioxybenzene and acid addition salts thereof useful as hypotensives. US4684651,1987
[105] Isaacson Scott A, Dampuam Alexander Y. Isolating multiple authentication channels, each using multiple authentication models.US200261895,2005
[106]苏冰,王雅丽. 1-(2-甲氧基苯基)哌嗪的合成改进.中国现代应用药学1999, 16(6):33-34
[107]吴义杰,周廷森. N-[4-[4-(4-甲氧基苯基)-1-哌嗪基]苯基]氨基甲酰肼的合成.中国医药工业杂志,1995, 29(9):415-416
[108] Lyon R. A., Titeler M., McKenney J. D., et al. Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergic agents. Journal of Medicinal Chemistry,1986, 29:630-634
[109]闫丽,董国君. 2-氯代苯并噻唑的合成研究.应用科技,2002, 29(9):65-66
[110] Li Jianqi , Hang. Liying, Zhang Chunnian, et al. Aralkyl-ketone piperazine derivatives and their uses as new antalgic or ataractic agent. CN1150176C,2004
[111] Marinho B. G., Miranda L. S., Gomes N. M., et al. Antinociceptive action of (+/-)-cis-(6-ethyl-tetrahydropyran-2-yl)-formic acid in mice. European Journal of Pharmacology,2006, 550:47-53
[112] Amresh G., Singh P. N., Rao Ch, Antinociceptive and antiarthritic activity of Cissampelos pareira roots. Journal of Ethnopharmacology,2007, 111:531-536