Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00152.X
J. Terron
The functional pharmacological properties of a group of quinoline-derivatives were screened for agonist activity at 5-HT1-like receptors mediating vasoconstriction. In experimental models predictive of antimigraine activity, 2-(2-aminoethyl) quinoline hydrochloride (D-1997) exhibited higher potency and efficacy at vasoconstrictor 5-HT1-like receptors than quipazine. D-1997 was also found to activate a novel vasoconstrictor mechanism in the carotid circulation. It is suggested D-1997 may represent a useful lead in the search for better acute antimigraine therapies.
{"title":"2-(2-aminoethyl)-quinoline (D-1997): A Novel Agonist at Craniovascular 5-HT1 Receptors Relevant to Migraine Therapy","authors":"J. Terron","doi":"10.1111/J.1527-3458.2000.TB00152.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00152.X","url":null,"abstract":"The functional pharmacological properties of a group of quinoline-derivatives were screened for agonist activity at 5-HT1-like receptors mediating vasoconstriction. In experimental models predictive of antimigraine activity, 2-(2-aminoethyl) quinoline hydrochloride (D-1997) exhibited higher potency and efficacy at vasoconstrictor 5-HT1-like receptors than quipazine. D-1997 was also found to activate a novel vasoconstrictor mechanism in the carotid circulation. It is suggested D-1997 may represent a useful lead in the search for better acute antimigraine therapies.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"14 1","pages":"267-277"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91256937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2004.TB00019.X
G. Farías, A. Fisher, N. Inestrosa
A loss of pre-synaptic cholinergic neurons, as observed in Alzheimer’s disease (AD), may lead to a decrease in M1 muscarinic receptor-mediated signaling. This, in turn, may affect an amyloid precursor protein processing and tau phosphorylation, two major features of AD. Defects in Wnt signaling have been postulated to contribute to the pathogenesis of the disease. How Wnt signaling may play a role in AD pathology remains to be elucidated. We report here that the activation of M1 receptor, by the M1 agonist AF267B, protects hippocampal neurons from amyloid-â-peptide and this effect involves the Wnt signaling pathway. The studies were carried out in primary cultures of rat hippocampal neurons, in the presence and absence of amyloid-â-peptide; plus and minus AF267B with and without pirenzepine, a selective M1 antagonist. Results indicate that AF267B protects neuronal cells as evaluated by the MTT reduction, immunofluorescence of neurofilaments and apoptotic analysis. To evaluate the role of the Wnt pathway on neuroprotection, we studied the stabilization of cytoplasmic and nuclear â-catenin, glycogen synthase kinase3-â activity as well as the expression of Wnt target genes. Results show that the neuroprotection induced by AF267B but not by the antagonist pirenzepine on the M1 mAChR is accomplished by the activation of the Wnt signaling pathway. We conclude that the cross talk between the M1 receptor signaling and the Wnt components underlie the neuroprotective effect of the M1 muscarinic agonist AF267B on rat hippocampal neurons. This may be highly relevant in the treatment of AD with M1 agonists. Supported by FONDAP-Biomedicine (No. 13980001) and Millennium Institute (MIFAB).
{"title":"Activation of M1 Muscarinic Receptors by AF267B Protects Hippocampal Neurons from Amyloid β Peptide Toxicity by Acting on the WNT Signalling","authors":"G. Farías, A. Fisher, N. Inestrosa","doi":"10.1111/J.1527-3458.2004.TB00019.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2004.TB00019.X","url":null,"abstract":"A loss of pre-synaptic cholinergic neurons, as observed in Alzheimer’s disease (AD), may lead to a decrease in M1 muscarinic receptor-mediated signaling. This, in turn, may affect an amyloid precursor protein processing and tau phosphorylation, two major features of AD. Defects in Wnt signaling have been postulated to contribute to the pathogenesis of the disease. How Wnt signaling may play a role in AD pathology remains to be elucidated. We report here that the activation of M1 receptor, by the M1 agonist AF267B, protects hippocampal neurons from amyloid-â-peptide and this effect involves the Wnt signaling pathway. The studies were carried out in primary cultures of rat hippocampal neurons, in the presence and absence of amyloid-â-peptide; plus and minus AF267B with and without pirenzepine, a selective M1 antagonist. Results indicate that AF267B protects neuronal cells as evaluated by the MTT reduction, immunofluorescence of neurofilaments and apoptotic analysis. To evaluate the role of the Wnt pathway on neuroprotection, we studied the stabilization of cytoplasmic and nuclear â-catenin, glycogen synthase kinase3-â activity as well as the expression of Wnt target genes. Results show that the neuroprotection induced by AF267B but not by the antagonist pirenzepine on the M1 mAChR is accomplished by the activation of the Wnt signaling pathway. We conclude that the cross talk between the M1 receptor signaling and the Wnt components underlie the neuroprotective effect of the M1 muscarinic agonist AF267B on rat hippocampal neurons. This may be highly relevant in the treatment of AD with M1 agonists. Supported by FONDAP-Biomedicine (No. 13980001) and Millennium Institute (MIFAB).","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"61 1","pages":"197-197"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78128755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00159.X
G. Rose
{"title":"Strategic Issues in the Discovery of Cognitive Enhancers","authors":"G. Rose","doi":"10.1111/J.1527-3458.2000.TB00159.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00159.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"8 1","pages":"3-3"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75389906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2001.TB00209.X
C. Roberts, J. Watson, Gary W. Price, D. Middlemiss
5-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5-HT1B receptor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro (furo[2,3-f]indole-3,4'-piperidine) hydrochloride). SB 236057-A has been shown to have high affinity for human 5-HT1B receptors (pK(i) = 8.2) and displays 80 or more fold selectivity for the human 5-HT1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT1B receptors SB-236057-A displayed inverse agonism (pA(2) = 8.9) using [(35)S]GTPgammaS binding, and silent antagonism (pA(2) = 9.2) using cAMP accumulation. SB-236057-A also acted as an antagonist at the 5-HT terminal autoreceptor as measured by [3H]5-HT release from electrically stimulated guinea pig and human cortical slices. In the guinea pig, pharmacokinetic analysis demonstrated that SB-236057-A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints. In vivo microdialysis studies demonstrated that SB-236057-A is an antagonist in the guinea pig cortex but has no effect on extracellular 5-HT levels per se. In contrast, SB-236057-A increased extracellular 5-HT levels in the guinea pig dentate gyrus. This increase in 5-HT release was comparable to that observed after 14 days of paroxetine administration. SB-236057-A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5-HT autoreceptor is of the 5-HT1B subtype. It appears that acute 5-HT1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.
{"title":"SB-236057-A: a selective 5-HT1B receptor inverse agonist.","authors":"C. Roberts, J. Watson, Gary W. Price, D. Middlemiss","doi":"10.1111/J.1527-3458.2001.TB00209.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2001.TB00209.X","url":null,"abstract":"5-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5-HT1B receptor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro (furo[2,3-f]indole-3,4'-piperidine) hydrochloride). SB 236057-A has been shown to have high affinity for human 5-HT1B receptors (pK(i) = 8.2) and displays 80 or more fold selectivity for the human 5-HT1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT1B receptors SB-236057-A displayed inverse agonism (pA(2) = 8.9) using [(35)S]GTPgammaS binding, and silent antagonism (pA(2) = 9.2) using cAMP accumulation. SB-236057-A also acted as an antagonist at the 5-HT terminal autoreceptor as measured by [3H]5-HT release from electrically stimulated guinea pig and human cortical slices. In the guinea pig, pharmacokinetic analysis demonstrated that SB-236057-A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints. In vivo microdialysis studies demonstrated that SB-236057-A is an antagonist in the guinea pig cortex but has no effect on extracellular 5-HT levels per se. In contrast, SB-236057-A increased extracellular 5-HT levels in the guinea pig dentate gyrus. This increase in 5-HT release was comparable to that observed after 14 days of paroxetine administration. SB-236057-A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5-HT autoreceptor is of the 5-HT1B subtype. It appears that acute 5-HT1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"28 1","pages":"433-44"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73631168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2001.TB00208.X
S. McGaraughty, M. Cowart, M. Jarvis
Adenosine (ADO) is an endogenous inhibitory neuromodulator that limits cellular excitability in response to tissue trauma and inflammation. Adenosine kinase (AK; EC 2.7.1.20) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. AK inhibitors have been shown to significantly increase ADO concentrations at sites of tissue injury and to provide effective antinociceptive, antiinflammatory, and anticonvulsant activity in animal models. Structurally novel nucleoside and non-nucleoside AK inhibitors that demonstrate high specificity for the AK enzyme compared with other ADO metabolic enzymes, transporters, and receptors have recently been synthesized. These compounds have also demonstrated improved cellular and tissue penetration compared with earlier tubercidin analogs. These compounds have been shown to exert beneficial effects in animal models of pain, inflammation and epilepsy with reduced cardiovascular side effects compared with direct acting ADO receptor (P1) agonists, thus supporting the hypothesis that AK inhibitors can enhance the actions of ADO in a site- and event-specific fashion.
{"title":"Recent developments in the discovery of novel adenosine kinase inhibitors: mechanism of action and therapeutic potential.","authors":"S. McGaraughty, M. Cowart, M. Jarvis","doi":"10.1111/J.1527-3458.2001.TB00208.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2001.TB00208.X","url":null,"abstract":"Adenosine (ADO) is an endogenous inhibitory neuromodulator that limits cellular excitability in response to tissue trauma and inflammation. Adenosine kinase (AK; EC 2.7.1.20) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. AK inhibitors have been shown to significantly increase ADO concentrations at sites of tissue injury and to provide effective antinociceptive, antiinflammatory, and anticonvulsant activity in animal models. Structurally novel nucleoside and non-nucleoside AK inhibitors that demonstrate high specificity for the AK enzyme compared with other ADO metabolic enzymes, transporters, and receptors have recently been synthesized. These compounds have also demonstrated improved cellular and tissue penetration compared with earlier tubercidin analogs. These compounds have been shown to exert beneficial effects in animal models of pain, inflammation and epilepsy with reduced cardiovascular side effects compared with direct acting ADO receptor (P1) agonists, thus supporting the hypothesis that AK inhibitors can enhance the actions of ADO in a site- and event-specific fashion.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"110 1","pages":"415-32"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87691215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00184.X
J. D. Kocsis
{"title":"Cell Transplantation Strategies to Repair the Injured Spinal Cord","authors":"J. D. Kocsis","doi":"10.1111/J.1527-3458.2000.TB00184.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00184.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"15 1","pages":"41-41"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89624105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2001.TB00201.X
W. J. Giardina, Michael Williams
Adrogolide (ABT-431; DAS-431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A-86929, a full agonist at dopamine D1 receptors. In in vitro functional assays, A-86929 is over 400 times more selective for dopamine D1 than D2 receptors. In rats with a unilateral loss of striatal dopamine, A-86929 produces contralateral rotations that are inhibited by dopamine D1 but not by dopamine D2 receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTP-lesioned marmosets, a model of Parkinson's disease (PD), and shows no tolerance upon repeated dosing for 28 days. In PD patients, intravenous (i.v.) adrogolide has antiparkinson efficacy equivalent to that of L-DOPA with a tendency towards a reduced liability to induce dyskinesia. The adverse events associated with its use were of mild-to-moderate severity and included injection site reaction, asthenia, headache, nausea, vomiting, postural hypotension, vasodilitation, and dizziness. Adrogolide can also attenuate the ability of cocaine to induce cocaine-seeking behavior and does not itself induce cocaine-seeking behavior in a rodent model of cocaine craving and relapse. In human cocaine abusers, i.v. adrogolide reduces cocaine craving and other cocaine-induced subjective effects. The results of animal abuse liability studies indicate that adrogolide is unlikely to have abuse potential in man. Adrogolide has also been reported to reverse haloperidol-induced cognitive deficits in monkeys, suggesting that it may be an effective treatment for the cognitive dysfunction associated with aging and disease. Adrogolide undergoes a high hepatic "first-pass" metabolism in man after oral dosing and, as a result, has a low oral bioavailability (approximately 4%). This limitation may potentially be circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase the bioavailability of adrogolide. As the first full dopamine D1 receptor agonist to show efficacy in PD patients and to reduce the craving and subjective effects of cocaine in cocaine abusers, adrogolide represents an important tool in understanding the pharmacotherapeutic potential of dopamine D1 receptor agonists.
Adrogolide (abt - 431;DAS-431)是一种化学稳定的前药，可在血浆中迅速(<1分钟)转化为a -86929, a -86929是多巴胺D1受体的完全激动剂。在体外功能测定中，A-86929对多巴胺D1的选择性比D2受体高400倍以上。在单侧纹状体多巴胺缺失的大鼠中，a -86929产生对侧旋转，这种旋转被多巴胺D1抑制，而不被多巴胺D2受体拮抗剂抑制。Adrogolide改善mptp损伤狨猴(帕金森病(PD)模型)的行为障碍和运动活动评分，并且在重复给药28天后显示无耐受性。在PD患者中，静脉注射阿德罗内酯具有与左旋多巴相当的抗帕金森疗效，并且倾向于减少诱发运动障碍的可能性。与其使用相关的不良事件为轻至中度严重程度，包括注射部位反应、虚弱、头痛、恶心、呕吐、体位性低血压、血管舒张和头晕。Adrogolide还可以减弱可卡因诱导可卡因寻求行为的能力，并且在可卡因渴求和复发的啮齿动物模型中本身不会诱导可卡因寻求行为。在人类可卡因滥用者中，静脉注射阿德罗内酯可以减少对可卡因的渴望和其他可卡因引起的主观影响。动物虐待责任研究的结果表明，阿德罗内酯不太可能对人类有滥用的可能性。阿德罗内酯也被报道可以逆转氟哌啶醇引起的猴子认知缺陷，这表明它可能是一种有效的治疗与衰老和疾病相关的认知功能障碍的方法。口服给药后，阿德罗内酯在人体内具有较高的肝脏“首过”代谢，因此其口服生物利用度较低(约为4%)。这一限制可能会被用于肺内输送的口服吸入制剂所规避，这种制剂大大增加了阿德罗内酯的生物利用度。作为首个对PD患者有效的全多巴胺D1受体激动剂，阿德罗内酯可以减少可卡因滥用者对可卡因的渴望和主观影响，是了解多巴胺D1受体激动剂药物治疗潜力的重要工具。
{"title":"Adrogolide HCl (ABT-431; DAS-431), a prodrug of the dopamine D1 receptor agonist, A-86929: preclinical pharmacology and clinical data.","authors":"W. J. Giardina, Michael Williams","doi":"10.1111/J.1527-3458.2001.TB00201.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2001.TB00201.X","url":null,"abstract":"Adrogolide (ABT-431; DAS-431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A-86929, a full agonist at dopamine D1 receptors. In in vitro functional assays, A-86929 is over 400 times more selective for dopamine D1 than D2 receptors. In rats with a unilateral loss of striatal dopamine, A-86929 produces contralateral rotations that are inhibited by dopamine D1 but not by dopamine D2 receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTP-lesioned marmosets, a model of Parkinson's disease (PD), and shows no tolerance upon repeated dosing for 28 days. In PD patients, intravenous (i.v.) adrogolide has antiparkinson efficacy equivalent to that of L-DOPA with a tendency towards a reduced liability to induce dyskinesia. The adverse events associated with its use were of mild-to-moderate severity and included injection site reaction, asthenia, headache, nausea, vomiting, postural hypotension, vasodilitation, and dizziness. Adrogolide can also attenuate the ability of cocaine to induce cocaine-seeking behavior and does not itself induce cocaine-seeking behavior in a rodent model of cocaine craving and relapse. In human cocaine abusers, i.v. adrogolide reduces cocaine craving and other cocaine-induced subjective effects. The results of animal abuse liability studies indicate that adrogolide is unlikely to have abuse potential in man. Adrogolide has also been reported to reverse haloperidol-induced cognitive deficits in monkeys, suggesting that it may be an effective treatment for the cognitive dysfunction associated with aging and disease. Adrogolide undergoes a high hepatic \"first-pass\" metabolism in man after oral dosing and, as a result, has a low oral bioavailability (approximately 4%). This limitation may potentially be circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase the bioavailability of adrogolide. As the first full dopamine D1 receptor agonist to show efficacy in PD patients and to reduce the craving and subjective effects of cocaine in cocaine abusers, adrogolide represents an important tool in understanding the pharmacotherapeutic potential of dopamine D1 receptor agonists.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"40 1","pages":"305-16"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77756823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2001.TB00192.X
A. Ottani, D. Giuliani
The synthetic compound HU 210 displays a multiplicity of biochemical, pharmacological, and behavioral effects, most of which have been demonstrated to be dependent on a selective agonistic activity at CB(1) and CB(2) cannabinoid receptors and to involve the main neurotransmitter systems. Results obtained in various studies suggest a potential clinical application of this highly potent drug (e.g., as antipyretic, antiinflammatory, analgesic, antiemetic, and antipsychotic agent) as well as its usefulness in research aimed to develop a better understanding of the involvement of the endogenous cannabinoid system in a number of physiopathological functions.
{"title":"Hu 210: a potent tool for investigations of the cannabinoid system.","authors":"A. Ottani, D. Giuliani","doi":"10.1111/J.1527-3458.2001.TB00192.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2001.TB00192.X","url":null,"abstract":"The synthetic compound HU 210 displays a multiplicity of biochemical, pharmacological, and behavioral effects, most of which have been demonstrated to be dependent on a selective agonistic activity at CB(1) and CB(2) cannabinoid receptors and to involve the main neurotransmitter systems. Results obtained in various studies suggest a potential clinical application of this highly potent drug (e.g., as antipyretic, antiinflammatory, analgesic, antiemetic, and antipsychotic agent) as well as its usefulness in research aimed to develop a better understanding of the involvement of the endogenous cannabinoid system in a number of physiopathological functions.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"9 1","pages":"131-45"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74413913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2001.TB00203.X
A. Scriabine
The meeting was organized and chaired by Giulio Maria Pasinetti, Associate Professor of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA. It was attended by ca. 150 physicians and basic medical scientists and consisted of 23 presentations on the effects of non-steroidal antiinflammatory drugs (NSAIDs), primarily cyclooxygenase 2 (COX-2) inhibitors, in Alzheimer’s disease (AD) and cancer. The meeting was supported by grants from Merck & Co. and Helsinn Healthcare. In his introductory remarks Pasinetti pointed out that there is substantial evidence that NSAIDs protect from colon cancer. They may also slow the progression of Alzheimer’s disease. He expressed hope that this meeting will provide an impetus for further evaluation and eventual use of NSAIDs in the therapy of these diseases. The first lecture, “Building a Better Aspirin, Experimental Approaches and Clinical Implications,” was delivered by D. L. DeWitt (Michigan State Univ., Lansing, MI, USA). He emphasized the importance of selective inhibition of COX-2 isoenzyme for side effect profile of inhibitors. Minor changes in the amino acid composition of COX-2, as compared to COX-1, increase the binding site pocket. Inhibitors with bulky side groups are more selective for COX-2 because they fit better to the larger binding site pocket. COX-2 inhibitors, unlike COX-1, do not require acidic side group for binding to the isoenzyme. The COX-2 + inhibitor complexes are not easily reversible, whereas binding of the inhibitors to COX-1 is freely reversible. There are also different modes of inhibition: time-dependent and competitive. Selective COX-2 inhibitors inhibit the isoenzyme time-dependently, the degree of inhibition increases with time. The same inhibitors may inhibit COX-1 competitively. At a low dose, aspirin is a selective COX-1 inhibitor. Among new COX-2 inhibitors valdeco-
会议由美国纽约州纽约西奈山医学院精神病学副教授Giulio Maria Pasinetti组织和主持。大约有150名医生和基础医学科学家参加了会议，其中包括23次关于非甾体抗炎药(NSAIDs)，主要是环氧化酶2 (COX-2)抑制剂在阿尔茨海默病(AD)和癌症中的作用的报告。这次会议得到了默克公司和赫尔辛基医疗公司的资助。帕西内蒂在他的开场白中指出，有大量证据表明非甾体抗炎药可以预防结肠癌。它们还可能减缓阿尔茨海默病的进展。他表示希望这次会议将为进一步评估和最终使用非甾体抗炎药治疗这些疾病提供动力。第一个讲座，“制造更好的阿司匹林，实验方法和临床意义”，由D. L. DeWitt(密歇根州立大学，Lansing, MI, USA)发表。他强调了选择性抑制COX-2同工酶对抑制剂副作用的重要性。与COX-1相比，COX-2氨基酸组成的微小变化增加了结合位点口袋。具有庞大侧基的抑制剂对COX-2更具选择性，因为它们更适合较大的结合位点口袋。COX-2抑制剂与COX-1不同，不需要酸性侧基与同工酶结合。COX-2 +抑制剂复合物不易可逆，而抑制剂与COX-1的结合是自由可逆的。还有不同的抑制模式:时间依赖性和竞争性。选择性COX-2抑制剂对同工酶的抑制具有时间依赖性，抑制程度随时间增加而增加。相同的抑制剂可能竞争性地抑制COX-1。低剂量阿司匹林是一种选择性COX-1抑制剂。新的COX-2抑制剂valdeco-
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