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Site specific 1:1 opioid:albumin conjugate with in vitro activity and long in vivo duration

BIOCONJUGATE CHEMISTRY 2000年第4期11卷 439-444页

作者： Holmes, DL Thibaudeau, K L'Archevêque, B Milner, PG Ezrin, AM Bridon, DP ConjuChem Inc Montreal PQ H2X 3Y8 Canada

A site-specific 1:1 dynorphin A-(1-13)-NH2 derivative conjugated specifically to Cys 34 on human serum albumin (CCI-1035) was shown to be an opioid receptor agonist in vitro and to be a long lasting antinociceptive agent when administered intravenously to mice as assessed by an acetic acid writhing assay. When 10 mu mol/kg of CCI-1035 was administered to mice, rapid antinociception was observed within 5 min following intravenous bolus injection and was sustained beyond 8 h. Antinociceptive activity was absent in a heat induced pain model using a mouse tail-flick assay. This finding represents the first report of a 1:1 albumin opioid conjugate retaining potent in vivo activity equal to or greater than dynorphin A, accompanied by a dramatic extension in duration of action. This novel site-specific bioconjugation technology produces an agent that may be useful for peripheral pain therapy.

关键词：氨基酸序列镇痛药/化学镇痛药/药理学 CHO细胞色谱法高压液相仓鼠亚科强啡肽类/化学分子序列数据肽碎片/化学血清白蛋白/化学动物人类小鼠

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1′,1′-dimethylheptyl-Δ-8-tetrahydrocannabinol-11-oic acid:: A novel, orally effective cannabinoid with analgesic and anti-inflammatory properties

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期291卷 31-38页

作者： Dajani, EZ Larsen, KR Taylor, J Dajani, NE Shahwan, TG Neeleman, SD Taylor, MS Dayton, MT Mir, GN Int Drug Dev Consultants Corp Long Grove IL 60047 USA Vet Affairs Med Ctr Dept Surg Salt Lake City UT 84148 USA Vet Affairs Med Ctr Dept Med Salt Lake City UT 84148 USA Univ Utah Sch Med Salt Lake City UT USA Drug Res Labs Buckingham PA USA

1',1'-Dimethylheptyl-Delta-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid that is under development by Atlantic Pharmaceuticals as an anti-inflammatory and analgesic drug. The objective of the study was to investigate the effects of CT-3 on overt symptom complex (Irwin's test), nociception, gastrointestinal (GI) ulceration, and pharmacological availability after intragastric (i.g.) and intraperitoneal (i.p.) administration. Analgesic studies were assessed in the hot-plate (55 degrees C) and the tail clip tests in mice and in the tail clip test in rats. In addition, pharmacological interaction of CT-3 with the solvent dimethyl sulfoxide (DMSO) was investigated in rats. In mice, CT-3 decreased spontaneous motor activity and induced dose-dependent, analgesic activity in the tail clip and hot-plate tests, with potency similar to morphine sulfate after i.g. and i.p. administration. However CT-3 showed more prolonged duration of analgesic action than morphine. In rats, CT-3 showed marked analgesia in the tail clip test and had similar i.p. and i.g. median effective dose (ED50 values;5 mg/kg). CT-3 was devoid of GI ulceration when administered with DMSO either acutely at doses below 100 mg/kg or chronically at a dosage of 30 mg/kg/day for 5 days. In contrast, indomethacin induced GI ulceration and deaths. The concurrent use of DMSO with CT-3 decreased its analgesic action, increased its adverse central nervous system effects, and induced GI ulceration. The evidence indicates that CT-3 exhibits a large dissociation between its anti-inflammatory/analgesic effects and its ulcerogenic actions. CT-3 warrants clinical development as a novel anti-inflammatory and analgesic drug.

关键词：投药口服镇痛镇痛药/药理学消炎药/药理学消炎药非甾类/药理学大麻酚类/药理学癌基底细胞/化学诱导二甲亚砜/药理学药物相互作用吲哚美辛/药理学注射腹腔内疼痛测定大鼠 Wistar 胃溃疡/化学诱导四氢大麻酚/类似物和衍生物四氢大麻酚/药理学动物男(雄)性小鼠大鼠

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Synthesis and analgesic activity of N-(N-acetyl-L-amino-acyl)-5-methoxytryptamines

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PREPARATIVE BIOCHEMISTRY & BIOTECHNOLOGY 2000年第1期30卷 39-47页

作者： Han, DM Wang, C Zhao, M Peng, SQ Beijing Med Univ Coll Pharmaceut Sci Beijing 100083 Peoples R China

5-Methoxytryptamine was acylated with N-acetyl-L-amino acids to give rise the corresponding N-(N-acetyl-L-amino acyl)-5-methoxytryptamines. The analgesic activity was evaluated by the tail flick test. Among the 6 compounds, the analgesic potency of N-(N-acetyl-tryptophanyl)-5-methoxytryptamine (5e) and N-(N-acetyl-glycyl)-5-methoxytryptamine (5a) are much more potent than that of melatonin.

关键词：镇痛药/化学合成镇痛药/化学镇痛药/药理学褪黑激素/药理学小鼠近交ICR 痛阈/药物作用色胺类/化学合成色胺类/化学动物男(雄)性小鼠

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Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a Xenopus oocyte expression system

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期291卷 618-626页

作者： McAllister, SD Griffin, G Satin, LS Abood, ME Virginia Commonwealth Univ Med Coll Virginia Dept Pharmacol & Toxicol Richmond VA 23298 USA

In this study, we focused on the pharmacological characterization of cannabinoid receptor coupling to G protein-gated inwardly rectifying potassium (GIRK) channels. Cannabinoids were tested on Xenopus laevis oocytes coexpressing the CB1 receptor and GIRK1 and GIRK4 channels (CB1/GIRK1/4) or the CB2 receptor and GIRK1/4 channels (CB2/GIRK1/4). WIN 55,212-2 enhanced currents carried by GIRK channels in the CB1/GIRK1/4 and CB2/GIRK1/4 system;however, the CB2 receptor did not couple efficiently to GIRK1/4 channels. In the CB1/GIRK1/4 system, WIN 55,212-2 was the most efficacious compound tested. CP 55,940 and anandamide acted as partial agonists. The rank order of potency was CP 55,940. WIN 55,212-2 = anandamide. The CB1-selective antagonist SR141716A alone acted as a inverse agonist by inhibiting GIRK currents in oocytes expressing CB1/GIRK1/4, suggesting the CB1 receptor is constitutively activated. A conserved aspartate residue, which was previously shown to be critical for G protein coupling in cannabinoid receptors, was mutated (to asparagine, D163N) and analyzed. Oocytes coexpressing CB1/GIRK1/4 or D163N/GIRK1/4 were compared. The potency of WIN 55,212-2 at the mutant receptor was similar to wild type, but its efficacy was substantially reduced. CP 55,940 did not elicit currents in oocytes expressing D163N/GIRK1/4. In summary, it appears the CB1 and CB2 receptors couple differently to GIRK1/4 channels. In the CB1/GIRK1/4 system, cannabinoids evaluated demonstrated the ability to enhance or inhibit GIRK currents. Furthermore, a conserved aspartate residue in the CB1 receptor is required for normal communication with GIRK channels in oocytes demonstrating the interaction between receptor and channels is G protein dependent.

关键词：镇痛药/药理学花生四烯酸类/药理学天冬酰胺钙通道阻滞药/药理学环己醇类/药理学剂量效应关系药物 GTP结合蛋白质类/代谢吗啉类/药理学突变萘类/药理学卵母细胞/生理学多不饱和脂肪酸酰胺类钾通道/药物作用钾通道/遗传学 RNA 互补/化学合成受体大麻酚受体药物/分类受体药物/生理学时间因素爪蟾属动物

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Pharmacogenetic evidence for the involvement of 5-hydroxytryptamine (serotonin)-1B receptors in the mediation of morphine antinociceptive sensitivity

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期291卷 444-449页

作者： Hain, HS Belknap, JK Mogil, JS Oregon Hlth & Sci Univ Vet Affairs Med Ctr Dept Behav Neurosci Portland OR 97201 USA Univ Illinois Dept Psychol Champaign IL 61820 USA Univ Illinois Neurosci Program Champaign IL 61820 USA

Morphine antinociception has been shown to be influenced significantly by genetic factors, now beginning to be identified in mice. A recent quantitative trait locus analysis revealed a significant statistical association between morphine antinociceptive magnitude and a region of mouse chromosome 9. This region contains the Htr1b gene, which encodes the 5-hydroxytryptamine (serotonin)-1B (5- HT1B) receptor subtype. To investigate the possibility that Htr1b represents the quantitative trait locus, C57BL/6 and DBA/2 inbred strains, the progenitors of the original quantitative trait locus mapping populations, were administered a novel 5- HT1B receptor antagonist (GR127935) concomitant with morphine. These mice are known to differ in morphine antinociceptive sensitivity on thermal pain assays (DBA/2 high;C57BL/6 low). GR127935 caused a dose-dependent antagonism (both reversal and prevention) of morphine antinociception in DBA/2 mice but had no effect in C57BL/6 mice. However, a 5-hydroxytryptamine-1A subtype (5- HT1A) receptor agonist, 8-hydroxydipropylaminotetralin, reversed morphine antinociception equally in the two strains. DBA/2 mice also exhibited significantly greater antinociception than did C57BL/6 mice from the administration of a 5- HT1B agonist, CGS12066. These data collectively support a role for 5- HT1B receptors in the mediation of morphine antinociception and support the contention that polymorphisms in the Htr1b gene may underlie individual differences in morphine sensitivity.

关键词： 8-羟-2-(二-n-丙胺)四氢萘/药理学镇痛药/药理学剂量效应关系药物药物相互作用小鼠近交C57BL 小鼠近交DBA 吗啡/药理学恶二唑类/药理学哌嗪类/药理学受体血清素/遗传学受体血清素/生理学敏感性与特异性血清素拮抗药/药理学种特异性时间因素动物小鼠

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GABA_B receptors couple to potassium and calcium channels on identified lateral perforant pathway projection neurons

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JOURNAL OF NEUROPHYSIOLOGY 2000年第2期83卷 1073-1078页

作者： Wang, XY Lambert, NA Med Coll Georgia Dept Pharmacol & Toxicol Augusta GA 30912 USA Vet Adm Med Ctr Med Res Serv Augusta GA 30912 USA

GABA(B) receptors couple to potassium and calcium channels on identified lateral perforant pathway projection neurons. J. Neurophysiol. 83: 1073-1078, 2000. Activation of presynaptic GABA(B) receptors inhibits neurotransmitter release at most cortical synapses, at least in part because of inhibition of voltage-gated calcium channels. One synapse where this is not the case is the lateral perforant pathway synapse onto dentate granule cells in the hippocampus. The current study was conducted to determine whether the neurons that make these synapses express GABA(B) receptors that can couple to ion channels. Perforant pathway projection neurons were labeled by injecting retrograde tracer into the dorsal hippocampus. The GABA(B) receptor agonist baclofen (10 mu M) activated inwardly rectifying potassium channels and inhibited currents mediated by voltage-gated calcium channels in retrogradely labeled neurons in layer II of the lateral entorhinal cortex. These effects were reversed by coapplication of the selective GABA(B) receptor antagonist CGP 55845A (1 mu M). Equivalent effects were produced by 100 mu M adenosine, which inhibits neurotransmitter release at lateral perforant pathway synapses. The effects of baclofen and adenosine on inward currents were largely occlusive. These results suggest that the absence of GABA(B) receptor-mediated presynaptic inhibition at lateral perforant pathway synapses is not simply due to a failure to express these receptors and imply that GABA(B) receptors can either be selectively localized or regulated at terminal versus somatodendritic domains.

关键词：腺苷/药理学镇痛药/药理学巴氯芬/药理学钙通道/生理学电生理学内嗅皮层/化学内嗅皮层/细胞学内嗅皮层/生理学 GABA激动剂/药理学 GABA拮抗剂/药理学膜电位/药物作用膜电位/生理学神经抑制/生理学神经元/化学神经元/生理学穿通通路/化学穿通通路/细胞学穿通通路/生理学次膦酸类/药理学钾通道/生理学丙醇胺类/药理学大鼠 Sprague-Dawley 受体 GABA-B/生理学突触/化学突触/生理学突触传递/药物作用突触传递/生理学动物大鼠

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Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期291卷 893-902页

作者： Mu, J Zhuang, SY Kirby, MT Hampson, RE Deadwyler, SA Wake Forest Univ Sch Med Dept Physiol & Pharmacol Ctr Neurobiol Invest Drug Abuse Winston Salem NC 27157 USA

Cannabinoid (CB1) receptor activation produced differential effects on voltage-gated outward potassium currents in whole-cell recordings from cultured (7-15 days) rat hippocampal neurons. Voltage-dependent potassium currents A (I-A) and D (I-D) were isolated from a composite tetraethylammonium-insensitive current (I-comp) by blockade with either 4-aminopyridine (500 mu M) or dendrotoxin (2 mu M) and subtraction of the residual I-A from I-comp to reveal I-D. The time constants of inactivation (tau) of I-A and I-D as determined in this manner were found to be quite different. The CB1 agonist WIN 55,212- 2 produced a 15- to 20-mV positive shift in voltage-dependent inactivation of I-A and a simultaneous voltage-independent reduction in the amplitude of I-D in the same neurons. The EC50 value for the effect of WIN 55,212- 2 on I-D amplitude (13.9 nM) was slightly lower than the EC50 value for its effect on I-A voltage dependence (20.6 nM). Pretreatment with either the CB1 antagonist SR141716A or pertussis toxin completely blocked the differential effects of WIN 55,212- 2 on I-A and I-D, whereas cellular dialysis with guanosine-5'-O-(3-thio) triphosphate mimicked the action of cannabinoids but blocked the action of simultaneously administered cannabinoid receptor ligands. Finally, the differential effects of cannabinoids on I-A and I-D were both shown to be mediated via the well documented cannabinoid receptor inhibition of adenylyl cyclase and subsequent modulation of cAMP and protein kinase. These actions are considered in terms of cAMP-mediated phosphorylation of separate I-A and I-D channels and the contribution of each to composite voltage-gated potassium currents in these cells.

关键词： 4-氨基吡啶/药理学镇痛药/药理学细胞培养的环AMP/药理学剂量效应关系药物药物相互作用眼镜蛇科毒液类/药理学胎儿/生理学海马/药物作用配体膜电位吗啉类/药理学萘类/药理学神经元/药物作用钾/药代动力学受体大麻酚受体药物/拮抗剂和抑制剂受体药物/生理学四乙基铵/药理学时间因素动物大鼠

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Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期290卷 214-219页

作者： Lu, Y Westlund, KN Univ Texas Med Branch Dept Anat & Neurosci Cell Biol Program Galveston TX 77555 USA Univ Texas Med Branch Inst Marine Biomed Galveston TX 77555 USA

In this study, we investigated the effectiveness of gabapentin (Neurontin), administered spinally with a microdialysis fiber, in reducing nociceptive behavioral responses induced by a knee joint inflammation model. This model is produced by injection of the knee joint with kaolin and carrageenan in rats. The resultant knee joint inflammation produces a secondary hyperalgesia to radiant heat applied to the hindpaw. Both pretreatment and post-treatment protocols were examined. Spinal administration of gabapentin (10 mg/ml) infused 1.5 h before induction of knee joint inflammation, although having no effect on the baseline, prevented the development of heat hyperalgesia. Gabapentin also prevented the development of other pain-related behaviors scored subjectively. Gabapentin had no effect, however, on the joint circumference increase typical in this model. In animals with fully developed knee joint inflammation, gabapentin produced a reversal of heat hyperalgesia. The paw withdrawal latency responses and subjective pain scores were no longer significantly different from baseline, but joint circumference increases remained. These data suggest that gabapentin is an effective antinociceptive agent when administered either before or after induction of knee joint inflammation acting through a central neurogenic mechanism.

关键词：乙酸盐类/投药和剂量乙酸盐类/药理学胺类镇痛药/投药和剂量镇痛药/药理学消炎药非甾类/投药和剂量消炎药非甾类/药理学关节炎实验性/化学诱导关节炎实验性/药物疗法关节炎实验性/病理生理学行为动物/药物作用角叉菜胶环己酸类剂量效应关系药物兴奋性氨基酸拮抗剂/投药和剂量兴奋性氨基酸拮抗剂/药理学后肢热温度/副作用痛觉过敏/药物疗法痛觉过敏/病因学痛觉过敏/病理生理学注射脊髓注射皮下关节/病理学白陶土疼痛测定/药物作用大鼠 Sprague-Dawley γ氨基丁酸动物大鼠

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γ-Aminobutyric acid_B receptors:: First of the functional metabotropic heterodimers

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期292卷 2-7页

作者： Bowery, NG Enna, SJ Univ Birmingham Sch Med Dept Pharmacol Birmingham B15 2TT W Midlands England Univ Kansas Sch Med Dept Pharmacol Toxicol & Therapeut Kansas City KS USA

Activation of the metabotropic gamma-aminobutyric acid(B) (GABA(B)) receptor increases K+ conductance and decreases Ca2+ channel activity in neuronal membranes. Studies with a number of new GABA(B) receptor agonists and antagonists reveal that in addition to their muscle relaxant effects, agonists display analgesic activity and reduce the craving for cocaine. With regard to GABA(B) receptor antagonists, preclinical data suggest they improve cognitive performance and possess antidepressant and antiepileptic potential. With a high-affinity GABA(B) antagonist, the structural properties of the receptor were characterized through expression cloning. Moreover, it has been found that expression of a fully functional GABA(B) receptor requires coupling between two separate and distinct gene products: GABA(B) R1 and GABA(B) R2. Besides being the first example of a functional heterodiameric metabotropic receptor, the components and molecular configuration of the GABA(B) receptor suggest novel mechanisms for producing pharmacologically distinct subtypes of G protein-coupled receptors.

关键词：镇痛药/药理学抗惊厥药/药理学抗抑郁药/药理学钙通道/代谢细胞膜/代谢克隆生物认知/药物作用 GABA激动剂/药理学 GABA拮抗剂/药理学 GTP结合蛋白质类/生理学肌松弛/生理学神经元/代谢钾/代谢受体 GABA-B/分类受体 GABA-B/生理学物质相关性障碍/预防和控制动物人类

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Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期288卷 1107-1116页

作者： Fairbanks, CA Wilcox, GL Univ Minnesota Dept Pharmacol Minneapolis MN 55455 USA Univ Minnesota Grad Program Neurosci Minneapolis MN 55455 USA

Morphine (Mor) tolerance has been attributed to a reduction of opioid-adrenergic antinociceptive synergy at the spinal level. The present experiments tested the interaction of intrathecally (i.t.) administered Mor-clonidine (Clon) combinations in mice made acutely or chronically tolerant to Mor. ICR mice were pretreated with Mor either acutely (40 nmol i.t., 8 h;100 mg/kg s.c., 4 h) or chronically (3 mg/kg s.c. every 6 h days 1 and 2;5 mg/kg s.c. every 6 h days 3 and 4). Antinociception was detected via the hot water (52.5 degrees C) tail-flick test. After the tail-flick latencies returned to baseline levels, dose-response curves were generated to Mor, Cion, and Mor-Clon combinations in tolerant and control mice. Development of tolerance was confirmed by significant rightward shifts of the Mor dose-response curves in tolerant mice compared with controls. Isobolographic analysis was conducted;the experimental combined ED50 values were compared statistically against their respective theoretical additive ED50 values. In all Mor-pretreated groups, the combination of Mor and Cion resulted in significant leftward shifts in the dose response curves compared with those of each agonist administered separately. In all tolerant and control groups, the combination of Mor and Cion produced an ED50 value significantly less than the corresponding theoretical additive ED50 value. Mor and Cion synergized in Mor-tolerant as well as in control mice. Spinally administered adrenergic/opioid synergistic combinations may be effective therapeutic strategies to manage pain in patients apparently tolerant to the analgesic effects of Mor.

关键词：镇痛药/药理学镇痛药阿片类/药理学可乐定/药理学剂量效应关系药物复方合剂药物协同作用药物耐受性注射脊髓注射皮下小鼠近交ICR 吗啡/投药和剂量吗啡/药理学尾时间因素动物男(雄)性小鼠

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