Pub Date : 2000-06-01DOI: 10.1211/146080800128736033
A. Izzo, Domenico Addeo, M. Amato, F. Borrelli, R. Capasso, G. Carlo, Emilia Nocerino, N. Mascolo, L. Pinto, F. Capasso
Cannabinoid CB1 receptors have been detected in several peripheral neurons, including those of the myenteric plexus. Activation of myenteric (prejunctional located) cannabinoid CB1 receptors decreased intestinal motility induced by electrical stimulation in the isolated guinea-pig and human ileum. In-vivo studies have shown that cannabinoid receptor agonists decreased gastrointestinal motility through activation of cannabinoid CB1 receptors, while SR141716A, a cannabinoid CB1-receptor antagonist, increased intestinal motility. Both central and peripheral cannabinoid CB1 receptors could modulate upper gastrointestinal, but the effect of systemic (intraperitoneally injected) cannabinoid drugs was mediated by peripheral receptors. In addition, the potency of cannabinoid receptor agonists was increased during inflammatory diarrhoea.
{"title":"In-vivo Modulation of Gastrointestinal Motility by Cannabinoid Drugs","authors":"A. Izzo, Domenico Addeo, M. Amato, F. Borrelli, R. Capasso, G. Carlo, Emilia Nocerino, N. Mascolo, L. Pinto, F. Capasso","doi":"10.1211/146080800128736033","DOIUrl":"https://doi.org/10.1211/146080800128736033","url":null,"abstract":"Cannabinoid CB1 receptors have been detected in several peripheral neurons, including those of the myenteric plexus. Activation of myenteric (prejunctional located) cannabinoid CB1 receptors decreased intestinal motility induced by electrical stimulation in the isolated guinea-pig and human ileum. \u0000 \u0000 \u0000 \u0000In-vivo studies have shown that cannabinoid receptor agonists decreased gastrointestinal motility through activation of cannabinoid CB1 receptors, while SR141716A, a cannabinoid CB1-receptor antagonist, increased intestinal motility. Both central and peripheral cannabinoid CB1 receptors could modulate upper gastrointestinal, but the effect of systemic (intraperitoneally injected) cannabinoid drugs was mediated by peripheral receptors. In addition, the potency of cannabinoid receptor agonists was increased during inflammatory diarrhoea.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73970969","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 : 2000-06-01DOI: 10.1211/146080800128736015
A. Ottani, D. Giuliani, F. Ferrari
To ascertain whether the cannabinoid agonist HU 210 (25, 50 or 100μ kg−1, i.p.) influenced rat spatial learning, animal performance was examined using the Morris water maze during and after treatments. Vocalization and wall-hugging, examples of unlearned behaviour, were examined also. HU 210 at 50 or 100μ kg−1 (once daily for four days, 60 min before a daily session) impaired learning; wall-hugging and enhanced vocalization were also displayed by the animals in the fourth session. When the drug treatment was discontinued, the effects produced by 50μ kg−1 HU 210 reversed in three days, while disruption of acquisition and vocalization caused by 100μ kg−1 HU 210 remained after seven days' abstinence. Rats sub-chronically treated with 100μ kg−1 HU 210 for ten days and then submitted to the water-maze task thirty days after last injection, did not differ with respect to controls in learning, memory, vocalization and wall-hugging. The anxiety-like state may be a specific factor contributing to the reversible impairment of spatial learning induced by HU 210.
为了确定大麻素激动剂HU 210(25、50或100μ kg - 1, i.p)是否影响大鼠的空间学习，在治疗期间和治疗后使用Morris水迷宫检查动物的表现。研究人员还研究了非习得行为的例子——发声和抱墙。剂量为50或100μ kg−1的HU 210(每天1次，连续4天，每日治疗前60分钟)会损害学习能力;在第四阶段，动物们也表现出了抱墙和增强的发声能力。停药后，50μ kg−1 HU 210的作用在3天后逆转，而100μ kg−1 HU 210对获取和发声的影响在停药7天后仍然存在。大鼠经100μ kg−1 HU 210亚慢性治疗10 d，最后一次注射30 d后再进行水迷宫任务，在学习、记忆、发声和抱壁方面与对照组没有差异。焦虑样状态可能是导致HU 210诱导的可逆性空间学习障碍的一个特定因素。
{"title":"Rat Cognitive Functions During and After Treatment with the Cannabinoid Agonist, HU 210","authors":"A. Ottani, D. Giuliani, F. Ferrari","doi":"10.1211/146080800128736015","DOIUrl":"https://doi.org/10.1211/146080800128736015","url":null,"abstract":"To ascertain whether the cannabinoid agonist HU 210 (25, 50 or 100μ kg−1, i.p.) influenced rat spatial learning, animal performance was examined using the Morris water maze during and after treatments. Vocalization and wall-hugging, examples of unlearned behaviour, were examined also. \u0000 \u0000HU 210 at 50 or 100μ kg−1 (once daily for four days, 60 min before a daily session) impaired learning; wall-hugging and enhanced vocalization were also displayed by the animals in the fourth session. When the drug treatment was discontinued, the effects produced by 50μ kg−1 HU 210 reversed in three days, while disruption of acquisition and vocalization caused by 100μ kg−1 HU 210 remained after seven days' abstinence. Rats sub-chronically treated with 100μ kg−1 HU 210 for ten days and then submitted to the water-maze task thirty days after last injection, did not differ with respect to controls in learning, memory, vocalization and wall-hugging. \u0000 \u0000The anxiety-like state may be a specific factor contributing to the reversible impairment of spatial learning induced by HU 210.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81394887","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 : 2000-06-01DOI: 10.1211/146080800128735999
N. Mascolo
In the light of current debate on cannabis “as a licensed drug”, this paper takes a balanced view of its potential therapeutic uses and its side-effect profile. In some medical conditions the use of cannabis seems to be beneficial to man. Despite some utility, the drug is not free from potential harm on the brain, lungs, immune and reproductive systems. One perspective would be the development of potent and selective cannabis-like drugs whose actions would be devoid of any negative effects.
{"title":"Medical Uses and Toxicological Profile of Cannabis","authors":"N. Mascolo","doi":"10.1211/146080800128735999","DOIUrl":"https://doi.org/10.1211/146080800128735999","url":null,"abstract":"In the light of current debate on cannabis “as a licensed drug”, this paper takes a balanced view of its potential therapeutic uses and its side-effect profile. In some medical conditions the use of cannabis seems to be beneficial to man. \u0000 \u0000 \u0000 \u0000Despite some utility, the drug is not free from potential harm on the brain, lungs, immune and reproductive systems. One perspective would be the development of potent and selective cannabis-like drugs whose actions would be devoid of any negative effects.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74082761","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 : 2000-06-01DOI: 10.1211/146080800128736042
G. L. Rana, Roberta Maria Lobello, D. Piomelli, A. Calignano
For centuries cannabis has been used for the management of pain, however, clinical studies have not led to a uniform idea regarding the analgesic effectiveness of cannabis and its constituent Δ9-tetrahydrocannabinol (Δ9-THC). The discovery of anandamide and 2-arachidonylglycerol, two endogenous ligands for cannabinoid receptors, has aroused interest about the possible role for these molecules in modulation of pain perception. The analgesic effects observed are mediated through cannabinoid receptors, localized in the brain, that interact with the noradrenergic and κ-opioid system; in the spinal cord, modulating the nociceptive perception, and on peripheral sensory neurons regulating the afferent stimulations. Anandamide is an effective antinociceptive agent, acting centrally as well as on peripheral neurons, modulating pain perception and initiation.
{"title":"Endocannabinoids and Peripheral Pain","authors":"G. L. Rana, Roberta Maria Lobello, D. Piomelli, A. Calignano","doi":"10.1211/146080800128736042","DOIUrl":"https://doi.org/10.1211/146080800128736042","url":null,"abstract":"For centuries cannabis has been used for the management of pain, however, clinical studies have not led to a uniform idea regarding the analgesic effectiveness of cannabis and its constituent Δ9-tetrahydrocannabinol (Δ9-THC). The discovery of anandamide and 2-arachidonylglycerol, two endogenous ligands for cannabinoid receptors, has aroused interest about the possible role for these molecules in modulation of pain perception. \u0000 \u0000 \u0000 \u0000The analgesic effects observed are mediated through cannabinoid receptors, localized in the brain, that interact with the noradrenergic and κ-opioid system; in the spinal cord, modulating the nociceptive perception, and on peripheral sensory neurons regulating the afferent stimulations. Anandamide is an effective antinociceptive agent, acting centrally as well as on peripheral neurons, modulating pain perception and initiation.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76823137","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 : 2000-05-01DOI: 10.1211/146080800128735881
F. Yamaki, Hikaru Tanaka, K. Shigenobu, Yoshio Tanaka
Vasorelaxant substances responsible for endothelium-dependent relaxation of pig coronary artery in response to noradrenaline have been investigated pharmacologically. Noradrenaline relaxed pig coronary artery in an endothelium- and concentration-dependent way in the presence of prazosin (10−6 M) and propranolol (3 times 10−6 M), to block α1- and β-adrenoceptors in smooth muscle cells. Prazosin- and propranolol-resistant endothelium-dependent relaxation of the coronary artery to noradrenaline was greatly attenuated by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (10−4 M) and the soluble guanylate cyclase inhibitor (1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, ODQ; 10−5 M). Noradrenaline-induced endothelium-dependent coronary relaxation in the presence of prazosin and propranolol was almost abolished by rauwolscine (3 times 10−6 M), a selective α2-adrenoceptor antagonist. These findings suggest that noradrenaline-induced endothelium-dependent relaxation of pig coronary artery is largely mediated by release of endothelium-derived NO as a consequence of the stimulation of endothelial α2-adrenoceptors.
{"title":"Nitric Oxide Accounts for Endothelium‐dependent Relaxation of Pig Coronary Artery in Response to Noradrenaline","authors":"F. Yamaki, Hikaru Tanaka, K. Shigenobu, Yoshio Tanaka","doi":"10.1211/146080800128735881","DOIUrl":"https://doi.org/10.1211/146080800128735881","url":null,"abstract":"Vasorelaxant substances responsible for endothelium-dependent relaxation of pig coronary artery in response to noradrenaline have been investigated pharmacologically. Noradrenaline relaxed pig coronary artery in an endothelium- and concentration-dependent way in the presence of prazosin (10−6 M) and propranolol (3 times 10−6 M), to block α1- and β-adrenoceptors in smooth muscle cells. Prazosin- and propranolol-resistant endothelium-dependent relaxation of the coronary artery to noradrenaline was greatly attenuated by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (10−4 M) and the soluble guanylate cyclase inhibitor (1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, ODQ; 10−5 M). Noradrenaline-induced endothelium-dependent coronary relaxation in the presence of prazosin and propranolol was almost abolished by rauwolscine (3 times 10−6 M), a selective α2-adrenoceptor antagonist. These findings suggest that noradrenaline-induced endothelium-dependent relaxation of pig coronary artery is largely mediated by release of endothelium-derived NO as a consequence of the stimulation of endothelial α2-adrenoceptors.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77712450","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 : 2000-05-01DOI: 10.1211/146080800128735908
Ying-Yu Chen, S. Doggrell
The aim of this study was to determine whether aortic membrane potential, or the effects of potassium chloride (KCl) and isoprenaline on that potential, were different in the spontaneously hypertensive rat (SHR), pre-hypertension and during hypertension. Thus we describe the effects of KCl and isoprenaline on the membrane potential of aortae from 5-and 14-week-old Wistar Kyoto normotensive rats (WKY) and SHR. Five-week-old SHR are prehypertensive. Membrane potentials and KCl-induced depolarization were similar for aortae from 5- and 14-week-old WKY and SHR. Isoprenaline at 10−8 M fully reversed KCl-induced depolarization in aortae from WKY but not in those from 5- and 14-week-old SHR. In conclusion, we have shown a selective defect in the capacity of isoprenaline to reverse KCl-induced depolarization in SHR pre- and during hypertension.
{"title":"Reduced Effects of Isoprenaline on the Membrane Potential of Aortic Smooth Muscle from Rats Pre‐ and During Hypertension","authors":"Ying-Yu Chen, S. Doggrell","doi":"10.1211/146080800128735908","DOIUrl":"https://doi.org/10.1211/146080800128735908","url":null,"abstract":"The aim of this study was to determine whether aortic membrane potential, or the effects of potassium chloride (KCl) and isoprenaline on that potential, were different in the spontaneously hypertensive rat (SHR), pre-hypertension and during hypertension. Thus we describe the effects of KCl and isoprenaline on the membrane potential of aortae from 5-and 14-week-old Wistar Kyoto normotensive rats (WKY) and SHR. Five-week-old SHR are prehypertensive. Membrane potentials and KCl-induced depolarization were similar for aortae from 5- and 14-week-old WKY and SHR. Isoprenaline at 10−8 M fully reversed KCl-induced depolarization in aortae from WKY but not in those from 5- and 14-week-old SHR. \u0000 \u0000 \u0000 \u0000In conclusion, we have shown a selective defect in the capacity of isoprenaline to reverse KCl-induced depolarization in SHR pre- and during hypertension.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86446091","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 : 2000-05-01DOI: 10.1211/146080800128735935
V. Agarwal, I. Reddy, M. Khan
The in-vitro stability of insulin in the presence of α-chymotrypsin and trypsin has been evaluated in the presence of different concentrations of chicken and duck ovomucoid (CkOVM and DkOVM), a new class of enzyme inhibitor derived from the egg white of avian species. The inhibitory effect was compared with that of aprotinin. The effectiveness of DkOVM was also determined in the presence of agents that accelerate α-chymotrypsin-mediated degradation of insulin in solution by deaggregation. Insulin solutions (18μM) were incubated at 37°C with 0.1 μM chymotrypsin and 0.5 μM trypsin in lOOmM Tris buffer containing 1 mM calcium chloride and different concentrations of CkOVM and DkOVM. Samples were treated with cold Tris containing 1% (v/v) trifluoroacetic acid to stop the enzyme action and analysed by reversed-phase high-performance liquid chromatography. Similar studies were performed with aprotinin, EDTA (0.05 mM) and sodium glycocholate (30mM) in the presence of α-chymotrypsin and DkOVM. DkOVM was effective against α-chymotrypsin-mediated degradation of insulin at enzyme-to-inhibitor ratios of 1:0–5, 1:1 and 1:2. CkOVM was ineffective against α-chymotrypsin even at an enzyme-to-inhibitor ratio of 1:4. In contrast, both DkOVM and CkOVM were completely effective against trypsin-mediated degradation of insulin at an enzyme-to-inhibitor ratio of 1:1. This effect was comparable with that of aprotinin at an enzyme-to-inhibitor ratio of 1:1. Inhibition of the enzyme was reduced in the presence of sodium glycocholate and EDTA. DkOVM effectively stabilized insulin against degradation for a study period of 1 h in the presence of α-chymotrypsin and trypsin. Because insulin is extensively degraded by α-chymotrypsin, DkOVM might be used to enhance the oral delivery of insulin.
{"title":"Oral Delivery of Proteins: Effect of Chicken and Duck Ovomucoid on the Stability of Insulin in the Presence of α‐Chymotrypsin and Trypsin","authors":"V. Agarwal, I. Reddy, M. Khan","doi":"10.1211/146080800128735935","DOIUrl":"https://doi.org/10.1211/146080800128735935","url":null,"abstract":"The in-vitro stability of insulin in the presence of α-chymotrypsin and trypsin has been evaluated in the presence of different concentrations of chicken and duck ovomucoid (CkOVM and DkOVM), a new class of enzyme inhibitor derived from the egg white of avian species. The inhibitory effect was compared with that of aprotinin. The effectiveness of DkOVM was also determined in the presence of agents that accelerate α-chymotrypsin-mediated degradation of insulin in solution by deaggregation. \u0000 \u0000 \u0000 \u0000Insulin solutions (18μM) were incubated at 37°C with 0.1 μM chymotrypsin and 0.5 μM trypsin in lOOmM Tris buffer containing 1 mM calcium chloride and different concentrations of CkOVM and DkOVM. Samples were treated with cold Tris containing 1% (v/v) trifluoroacetic acid to stop the enzyme action and analysed by reversed-phase high-performance liquid chromatography. Similar studies were performed with aprotinin, EDTA (0.05 mM) and sodium glycocholate (30mM) in the presence of α-chymotrypsin and DkOVM. DkOVM was effective against α-chymotrypsin-mediated degradation of insulin at enzyme-to-inhibitor ratios of 1:0–5, 1:1 and 1:2. CkOVM was ineffective against α-chymotrypsin even at an enzyme-to-inhibitor ratio of 1:4. In contrast, both DkOVM and CkOVM were completely effective against trypsin-mediated degradation of insulin at an enzyme-to-inhibitor ratio of 1:1. This effect was comparable with that of aprotinin at an enzyme-to-inhibitor ratio of 1:1. Inhibition of the enzyme was reduced in the presence of sodium glycocholate and EDTA. \u0000 \u0000 \u0000 \u0000DkOVM effectively stabilized insulin against degradation for a study period of 1 h in the presence of α-chymotrypsin and trypsin. Because insulin is extensively degraded by α-chymotrypsin, DkOVM might be used to enhance the oral delivery of insulin.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79228694","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 : 2000-05-01DOI: 10.1211/146080800128735917
Zi‐Jiang Chen, D. Che, Chung‐ho Chang
Resveratrol, found in wine and grapes, has cardioprotective and anticarcinogenic properties. The guanylate cyclase-cyclic GMP (cGMP) system is known to mediate the effects of vasoactive hormone and ligands such as atrial natriuretic factor and nitric oxide. It is possible that resveratrol exerts its effects by activating guanylate cyclase. This study was conducted to examine whether resveratrol can affect the guanylate cyclase-cGMP system in PC12 cells. The results showed that resveratrol dose-dependently increased cGMP levels. It inhibited membrane-bound guanylate cyclase activity stimulated by atrial natriuretic factor, but had no effect on soluble guanylate cyclase activity stimulated by sodium nitroprusside. It also directly stimulated membrane-bound guanylate cyclase activity in PC12 cell membranes. These results show that resveratrol increases cGMP formation by activating membrane-bound, but not soluble, guanylate cyclase.
{"title":"Resveratrol Activates Membrane‐bound Guanylate Cyclase in PC12 Cells","authors":"Zi‐Jiang Chen, D. Che, Chung‐ho Chang","doi":"10.1211/146080800128735917","DOIUrl":"https://doi.org/10.1211/146080800128735917","url":null,"abstract":"Resveratrol, found in wine and grapes, has cardioprotective and anticarcinogenic properties. The guanylate cyclase-cyclic GMP (cGMP) system is known to mediate the effects of vasoactive hormone and ligands such as atrial natriuretic factor and nitric oxide. It is possible that resveratrol exerts its effects by activating guanylate cyclase. This study was conducted to examine whether resveratrol can affect the guanylate cyclase-cGMP system in PC12 cells. \u0000 \u0000The results showed that resveratrol dose-dependently increased cGMP levels. It inhibited membrane-bound guanylate cyclase activity stimulated by atrial natriuretic factor, but had no effect on soluble guanylate cyclase activity stimulated by sodium nitroprusside. It also directly stimulated membrane-bound guanylate cyclase activity in PC12 cell membranes. \u0000 \u0000These results show that resveratrol increases cGMP formation by activating membrane-bound, but not soluble, guanylate cyclase.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90772925","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 : 2000-05-01DOI: 10.1211/146080800128735926
M. Jung, A. Wahl, W. Neupert, G. Geisslinger, P. Senter
The synthesis of fluorinated derivatives of the sulphide and sulphone metabolites of sulindac, a non-steroidal anti-inflammatory agent with chemopreventative activity, is reported. The key step in the synthesis is a Pummerer-rearrangement of the parent sulindac sulphoxide using (diethylamino)sulphur trifluoride as an activating agent and as a source of the fluoride nucleophile. The reaction leads to the formation of the 4-fluoromethylthio and 4-fluoromethylsulphonyl derivatives of sulindac (4a and 4b, respectively). Sulindac sulphide is 2.5 times more potent as a COX-1 inhibitor compared with its fluorinated counterpart 4a. The sulphones were inactive as COX-1 inhibitors, and none of the compounds inhibited COX-2 concentrations up to 0.1 mM. Cytotoxicity assays showed that 4a and 4b were as cytotoxic as sulindac sulphide and sulindac sulphone on 3719 colorectal carcinoma cell lines. Compound 4b was the most potent compound on RCA cells with an IC50 of 95 μM (sulindac sulphide 140μM, sulindac sulphone 175 μM). Fluorinated sulindac derivatives warrant further investigation since we have shown that cytotoxic activity can be retained or even increased independently from COX-inhibitory properties. This could help minimize the undesired side-effects associated with chronic sulindac administration.
{"title":"Synthesis and Activity of Fluorinated Derivatives of Sulindac Sulphide and Sulindac Sulphone","authors":"M. Jung, A. Wahl, W. Neupert, G. Geisslinger, P. Senter","doi":"10.1211/146080800128735926","DOIUrl":"https://doi.org/10.1211/146080800128735926","url":null,"abstract":"The synthesis of fluorinated derivatives of the sulphide and sulphone metabolites of sulindac, a non-steroidal anti-inflammatory agent with chemopreventative activity, is reported. \u0000 \u0000 \u0000 \u0000The key step in the synthesis is a Pummerer-rearrangement of the parent sulindac sulphoxide using (diethylamino)sulphur trifluoride as an activating agent and as a source of the fluoride nucleophile. The reaction leads to the formation of the 4-fluoromethylthio and 4-fluoromethylsulphonyl derivatives of sulindac (4a and 4b, respectively). Sulindac sulphide is 2.5 times more potent as a COX-1 inhibitor compared with its fluorinated counterpart 4a. The sulphones were inactive as COX-1 inhibitors, and none of the compounds inhibited COX-2 concentrations up to 0.1 mM. Cytotoxicity assays showed that 4a and 4b were as cytotoxic as sulindac sulphide and sulindac sulphone on 3719 colorectal carcinoma cell lines. Compound 4b was the most potent compound on RCA cells with an IC50 of 95 μM (sulindac sulphide 140μM, sulindac sulphone 175 μM). \u0000 \u0000 \u0000 \u0000Fluorinated sulindac derivatives warrant further investigation since we have shown that cytotoxic activity can be retained or even increased independently from COX-inhibitory properties. This could help minimize the undesired side-effects associated with chronic sulindac administration.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83167017","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 : 2000-05-01DOI: 10.1211/146080800128735872
H. Pae, Yoo-hyun Kim, Y. Shin, Jae-Heon Yang, J. Eun, Hun-taeg Chung
Inappropriate release of nitric oxide (NO) has been linked to the pathogenesis of several disease states. Glucocorticoids inhibit the synthesis of NO and could be effective in the treatment of NO-mediated diseases. We show the protective effect of dexamethasone on NO-induced apoptosis in leukaemia HL-60 cells in man. Agarose electrophoresis of the DNA extracted from HL-60 cells resulted in a ladder-like pattern of fragmentation after 6-and 9-h exposure of the cells to 1 mM S-nitrosoglutathione, a physiologically relevant NO donor. Pre-incubation of the cells with 1 μM dexamethasone for 6 h blocked NO-induced DNA fragmentation. This effect was abolished by RU-486, a steroid receptor antagonist, and cycloheximide, a protein synthesis inhibitor, suggesting that the protective effect of dexamethasone might require glucocorticoid receptor binding and protein synthesis. Concerning NO signal transduction, we found that dexamethasone efficiently prevented NO-induced activation of caspase-3 proteases, suggesting an inhibitory mechanism upstream of the terminal death pathway. Collectively, these findings highlight a novel protective effect of dexamethasone on NO-mediated cellular injury.
一氧化氮(NO)的不适当释放与几种疾病状态的发病机制有关。糖皮质激素抑制NO的合成，可有效治疗NO介导的疾病。我们研究了地塞米松对no诱导的人白血病HL-60细胞凋亡的保护作用。从HL-60细胞中提取的DNA琼脂糖电泳结果显示，在细胞暴露于1 mM s -亚硝基谷胱甘肽(生理上相关的NO供体)6和9小时后，细胞呈阶梯状断裂。1 μM地塞米松预处理6 h，可阻断no诱导的DNA断裂。这种作用被类固醇受体拮抗剂RU-486和蛋白质合成抑制剂环己亚胺消除，提示地塞米松的保护作用可能需要糖皮质激素受体结合和蛋白质合成。在NO信号转导方面，我们发现地塞米松有效地阻止了NO诱导的caspase-3蛋白酶的激活，提示其抑制机制位于终末死亡途径的上游。总的来说，这些发现强调了地塞米松对no介导的细胞损伤的一种新的保护作用。
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