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3-aryl-2-carbomethoxybicyclooct-2-enes inhibit WIN 35,428 binding potently and selectively at the dopamine transporter

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BIOORGANIC & MEDICINAL CHEMISTRY 2000年第3期8卷 581-590页

作者： Meltzer, PC Blundell, P Huang, H Liu, SH Yong, YF Madras, BK Organix Inc Woburn MA 01801 USA Harvard Univ Sch Med Dept Psychiat Southborough MA 01772 USA New England Reg Primate Ctr Southborough MA 01772 USA

The search for medications for cocaine abuse has focused upon the design of potential cocaine antagonists or cocaine substitutes which interact at the dopamine transporter of mammalian systems. This manuscript describes the synthesis and biological evaluation of 8-substituted 2-carbomethoxy-3-arylbicyclo[3.2.1]oct-2-enes. These compounds prove potent and selective inhibitors of the dopamine transporter. Their selectivity results primarily from a reduced inhibitory potency toward the serotonin transporter. This work supports the notion that the orientation of the 3-aryl ring in the bicyclo[3.2,1]octane system affects the interaction of these molecules with the serotonin transporter far more markedly than it affects the interaction with the dopamine transporter. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：结合竞争性脑化学载体蛋白质类/代谢西酞普兰/拮抗剂和抑制剂西酞普兰/代谢可卡因/类似物和衍生物可卡因/拮抗剂和抑制剂可卡因/代谢多巴胺质膜转运蛋白质类多巴胺摄取抑制剂/化学合成多巴胺摄取抑制剂/代谢成束猴膜糖蛋白类/代谢膜转运蛋白质类分子结构神经组织蛋白质类血清素质膜转运蛋白质类立体异构现象构效关系氚动物女(雌)性男(雄)性

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Catalytic antibodies that hydrolyze (-)-cocaine obtained by a high-throughput procedure

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期293卷 952-961页

作者： Cashman, JR Berkman, CE Underiner, GE Human BioMol Res Inst San Diego CA 92121 USA

Antibodies to a 2 beta-carboxamido-2 beta-phosphonate transition-state analog of (-)-cocaine benzoate ester hydrolysis were elicited in mice. A large number of hybridoma cell lines were propagated, and the catalytic activity of culture fluid was determined with a high-throughput photometric assay using cocaine benzoyl thioester as substrate. Binding avidity of the hybridoma supernatants to the phosphonate hapten was also determined. The initial rate constants for cocaine benzoyl thioester hydrolysis and binding avidity for a large number of hybridoma supernatants elicited to the phosphonate hapten did not always correlate. The lack of correlation of substrate hydrolysis with the binding affinity of 70 catalytic antibodies was also observed for (-)-cocaine hydrolysis using derivatization and HPLC analysis of methyl ecgonine as meta-nitrococaine. The k(cat) values for cocaine benzoyl thioester hydrolysis by monoclonal antibodies 3, 5, and 12 were 38, 4.2, and 0.6 min(-1), respectively. For monoclonal antibody 5, the selectivity ratios (K-i value divided by the K-m value for the hydrolysis of cocaine benzoyl thioester) with ecgonine benzoyl ester, ecgonine methyl ester, norcocaine, and ecgonine were 101, 25, 9.4, and 4, respectively. Three active esterolytic monoclonal antibodies identified with the high-throughput assay procedure were examined in detail for their ability to hydrolyze (-)-cocaine. The k(cat) values for the hydrolysis of (-)-cocaine with monoclonal antibodies 3, 5, and 12 were 6.6, 0.4, and 0.1 min(-1), respectively. Hydrolysis of (-)-cocaine by monoclonal antibody 3 approached the k(cat) value for that of human butyrylcholinesterase. Cocaine esterolytic catalytic antibodies that approach or exceed the catalytic efficiency of human butyrylcholinesterase may represent a new pharmacological intervention approach to the treatment of cocaine abuse, and the high-throughput process described here represents an advance in the effort to develop clinically usefu

关键词：抗体单克隆/免疫学催化作用可卡因/类似物和衍生物可卡因/代谢杂交瘤/代谢氢离子浓度水解酶类/代谢水解作用动力学小鼠近交BALBC 动物小鼠

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Presynaptic and postsynaptic dopaminergic binding densities in the nigrostriatal and mesocortical systems in early Parkinson's disease: A double-tracer positron emission tomography study

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ANNALS OF NEUROLOGY 1999年第5期46卷 723-731页

作者： Ouchi, Y Kanno, T Okada, H Yoshikawa, E Futatsubashi, M Nobezawa, S Torizuka, T Sakamoto, M Hamamatsu Med Ctr Positron Med Ctr Hirakuchi Hamakita 4340041 Japan Hamamatsu Med Ctr Dept Neurol Hirakuchi Hamakita 4340041 Japan Hamamatsu Photon KK Cent Res Labs Hirakuchi Japan

To investigate changes in the relation between presynaptic and postsynaptic dopaminergic functions in vivo in both nigrostriatal and mesocortical systems in Parkinson's disease (PD), 10 drug-naive early PD patients were studied twice using positron emission tomography with [C-11]CFT (dopamine transporter probe) followed by [C-11]SCH 23390 (D1 receptor probe). Regional binding potentials (k(3)/k(4)) of [C-11]CFT and [C-11]SCH 23390 in the striatum (nigrostriatal system) and the orbitofrontal cortex (mesocortical system) were estimated by compartment analyses. Levels of [C-11]CFT k(3)/k(4) in the two projection areas were shown to be significantly lower in PD, whereas [C-11]SCH 23390 levels remained unchanged. Regression analysis showed that estimates of CFT k(3)/k(4) were positively correlated with those of SCH 23390 k(3)/k(4) in the striatum in normal control, whereas the two binding estimates were less positively correlated in the caudate and inversely correlated in the putamen in PD. No significant correlation was observed in the orbitofrontal cortex in both groups. These results indicated that dopamine transporters and D1 receptors change in parallel in the normal striatal synapses, but the association becomes asymmetrical because of reduction in presynaptic and relative elevation in postsynaptic markers in PD. Alterations in synaptic parallel regulation in the nigrostriatal system might reflect early pathophysiology in the parkinsonian brain.

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Cocaine and alcohol interactions in the rat: Effect of cocaine and alcohol pretreatments on cocaine pharmacokinetics and pharmacodynamics

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第12期88卷 1266-1274页

作者： Pan, WJ Hedaya, MA Washington State Univ Coll Pharm Dept Pharmaceut Sci Pharmacol Toxicol Grad Program Pullman WA 99164 USA

This experiment was designed to investigate the effect of pretreatment with cocaine and alcohol on cocaine pharmacokinetics and pharmacodynamics. Four groups of rats (n = 8 per group) received one of the following pretreatments for two weeks: none, alcohol (10% v/v in drinking water), cocaine (15 mg/kg/day ip), and alcohol+cocaine (10% v/v in drinking water+15 mg/kg/day ip). On the day of the experiment, cocaine was administered (30 mg/kg, ip) to each rat, either alone or in combination with alcohol (5 g/kg, po), in a balanced crossover experimental design. Plasma and brain ECF concentrations of cocaine and its three metabolites: benzoylecgonine, norcocaine, and cocaethylene were assayed by HPLC-UV. The percent change in brain dopamine concentration, mean arterial blood pressure, and heart rate were determined simultaneously. A sigmoid-E-max model was used to describe the brain cocaine concentration-neurochemical effect (dopamine) relationship, and an indirect pharmacodynamic response model was used to describe the plasma cocaine concentration-cardiovascular effect relationships. Alcohol pretreatment led to significant increase in cocaine AUC(p), alpha(t1/2), and beta(t1/2) Cocaine pretreatment significantly increased cocaine bioavailability, absorption rate constant, TBC, and the formation clearance of cocaethylene. Acute alcohol coadministration with cocaine increased cocaine AUC(p) and bioavailability, reduced the fraction of cocaine dose converted to benzoylecgonine, and increased the formation of norcocaine. These results indicate that the pharmacokinetics of cocaine, either administered alone or in combination with alcohol, is significantly altered due-to prior cocaine and/or alcohol use. Both cocaine and alcohol pretreatments increased the E-max for dopamine, with no effect on the EC50 Acute alcohol coadministration with cocaine significantly increased the E-max for dopamine and reduced the EC50. Cocaine pretreatment significantly decreased the I-max far bloo

关键词：算法曲线下面积生物转化血压/药物作用脑化学/药物作用中枢神经系统抑制药/药理学色谱法高压液相可卡因/类似物和衍生物可卡因/血液可卡因/代谢可卡因/药代动力学可卡因/药理学多巴胺/代谢多巴胺摄取抑制剂/血液多巴胺摄取抑制剂/药代动力学多巴胺摄取抑制剂/药理学药物相互作用乙醇/药理学心率/药物作用模型生物学大鼠 Wistar 动物男(雄)性大鼠

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Sulfonium salts as derivatizing agents. 3. Quantitation of the cocaine metabolite benzoylecgonine in urine using gas chromatography with ion-pair extraction/on-column alkylation

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JOURNAL OF ANALYTICAL TOXICOLOGY 1999年第7期23卷 581-585页

作者： Panganiban, K Jacob, P Everhart, ET Tisdale, EC Batki, SL Mendelson, JE Jones, RT Univ Calif San Francisco Dept Psychiat Drug Dependence Res Ctr San Francisco CA 94143 USA

Recent studies have demonstrated the utility of quantitative assays for benzoylecgonine in assessing the efficacy of cocaine-dependence-treatment programs to determine if the amount of cocaine consumed has been reduced. We describe a simple gas chromatographic method for determining benzoylecgonine concentrations in urine. BZE is extracted from urine as an ion pair with tri-n-propylsulfonium ion. Injection into the heated injection port of the gas chromatograph results in thermal conversion of the ion pair to the n-propyl ester of BZE. Using the structural analogue of BZE, m-loluylecgonine, as the internal standard, the analysis is carried out on a (5% phenyl) methylpolysiloxane capillary column with nitrogen-phosphorus detection. There was a good correlation between BZE concentrations determined by gas chromatography-mass spectrometry and concentrations determined by the method described in this paper. Application to cocaine-dependence-treatment programs is discussed. ? Previous | Next Article ?Table of Contents This Article J Anal Toxicol (November-December 1999) 23 (7): 581-585. doi: 10.1093/jat/23.7.581? Free Full Text (PDF)Free Classifications ArticlesServices Alert me when cited Alert me if corrected Find similar articles Similar articles in Web of Science Similar articles in PubMed Add to my archive Download citation Request Permissions Citing Articles Load citing article information Citing articles via CrossRef Citing articles via Scopus Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Panganiban, K. Articles by Jones, R. T. Search for related content PubMed PubMed citation Articles by Panganiban, K. Articles by Jacob, P. Articles by Everhart, E. T. Articles by Tisdale, E. C. Articles by Batki, S. L. Articles by Mendelson, J. E. Articles by Jones, R. T. Related Content Load related web page information ShareEmail this article CiteULike Delicious Facebook Google+ Mendeley TwitterWhat's this?

关键词：烷化作用色谱法气相/方法可卡因/类似物和衍生物可卡因/化学可卡因/尿可卡因相关性障碍/尿气相色谱-质谱法/方法物质滥用检测/方法锍化合物/化学

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Cocaine vaccines: Antibody protection against relapse in a rat model

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第11期97卷 6202-6206页

作者： Carrera, MRA Ashley, JA Zhou, B Wirsching, P Koob, GF Janda, KD Scripps Res Inst Res Inst Dept Chem La Jolla CA 92037 USA Scripps Res Inst Res Inst Dept Neuropharmacol La Jolla CA 92037 USA Scripps Res Inst Res Inst Dept Mol Biol La Jolla CA 92037 USA

The efficacy of active immunization with the cocaine immunogen GNC-keyhole limpet hemocyanin (KLH) in preventing cocaine self-administration reinstatement was assessed in rats. An animal model of relapse was used where rats were trained to self-administer cocaine, subjected to a period of extinction by substituting the drug for saline, vaccinated, and re-exposed to cocaine. Compared with controls, animals immunized with GNC-KLH did not reinstate cocaine self-administration behavior when given a noncontingent cocaine infusion on two consecutive days. Upon double and triple infusions, 38-62% of vaccinated animals failed to reinstate as compared with full reinstatement in all control animals. Exposure to ad libitum cocaine reinstated baseline values in control animals and resulted in double to triple the baseline values of self-infusions in vaccinated animals, suggesting a partial antibody-mediated blockade of cocaine access to the central nervous system, This compensating effect was blocked by passive immunization pretreatment with the monoclonal IgG GNC92H2 in both vaccinated and control groups, To further assess the surmountability potential of GNC-KLH-induced antibody titers by cocaine self-administration, and the capacity of these titers to block the reinforcing effects of the drug, rats were tested at various doses of cocaine (0.015-0.5 mg/infusion). Active immunization with GNC-KLH produced approximately an 8-fold rightward shift of the dose-effect function for cocaine. The results reported suggest that immunopharmacotherapy may offer a promising means to treat cocaine abuse by aiding in the prevention of relapse.

关键词：抗体单克隆/免疫学可卡因/投药和剂量可卡因/类似物和衍生物可卡因/免疫学可卡因/毒性可卡因相关性障碍/预防和控制可卡因相关性障碍/治疗剂量效应关系免疫免疫法免疫法被动大鼠 Wistar 复发强化(心理学) 自我遵嘱服药接种疫苗动物男(雄)性大鼠

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期288卷 1334-1339页

作者： Hebert, MA Larson, GA Zahniser, NR Gerhardt, GA Univ Colorado Hlth Sci Ctr Dept Psychiat Denver CO 80262 USA Univ Colorado Hlth Sci Ctr Dept Pharmacol Denver CO 80262 USA Univ Colorado Hlth Sci Ctr Neurosci Training Program Denver CO 80262 USA Univ Colorado Hlth Sci Ctr Rocky Mt Ctr Sensor Technol Denver CO 80262 USA

In the present study, we used the potent cocaine analog [H-3]WIN 35,428 to map and quantify binding to the dopamine transporter (DAT) within the dorsal striatum, nucleus accumbens, substantia nigra, and ventral tegmental area in young (6-month-old), middle-aged (12-month-old), and aged (18- and 24-month-old) Fischer 344 rats. Quantitative autoradiographic analysis of indirect [H-3]WIN 35,428 saturation curves revealed two-site binding for all four brain regions in every age group. The percentage of binding to the high- or low-affinity sites did not differ with age or region and was approximately 50%. However, significant age-related decreases in the overall density (B-max) of [H-3]WIN 35,428-binding sites were observed in the striatum, nucleus accumbens, substantia nigra, and ventral tegmental area. The B-max within all brain regions declined by more than 15% every 6 months, with the B-max in the aged (24-month-old) group being approximately halt that measured in the young adult (6-month-old) group. Competition experiments indicated that nomifensine also exhibited two-site binding to the DAT in Fischer 344 rats. No consistent age-related differences in binding affinities were noted with either [H-3]WIN 35,428 or nomifensine. Taken together, these results support the hypothesis that functional DATs within the nigrostriatal and mesolimbic systems are down-regulated with age, without changing their affinity for ligands.

关键词：年龄因素放射自显影术结合竞争性脑/代谢载体蛋白质类/代谢可卡因/类似物和衍生物可卡因/代谢多巴胺质膜转运蛋白质类多巴胺摄取抑制剂/代谢膜糖蛋白类膜转运蛋白质类神经组织蛋白质类诺米芬辛/代谢伏核/代谢大鼠近交F344 黑质/代谢氚腹侧被盖区/代谢动物男(雄)性大鼠

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Effects of sex and gonadectomy on cocaine metabolism in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期290卷 1316-1323页

作者： Bowman, BP Vaughan, SR Walker, QD Davis, SL Little, PJ Scheffler, NM Thomas, BF Kuhn, CM Duke Univ Med Ctr Dept Pharmacol Durham NC 27710 USA Res Triangle Inst Res Triangle Pk NC 27709 USA

The purpose of the current study is to determine whether sex differences in metabolism of cocaine (COC) exist that could contribute to the greater behavioral sensitivity of females to COC administration. To investigate this question, concentrations of COC and its two principle metabolites benzoylecgonine (BE) and ecgonine methyl ester (EME) were measured by gas chromatography/mass spectroscopy in brain and plasma collected from male and female vats that were sacrificed between 5 and 90 min after injection COC (15 mg/kg i.p.). COC concentrations did not differ in plasma or brain tissue of males and females, but sex-specific patterns of metabolite distribution were detected. BE was 2-fold higher in plasma and brain of males than females, whereas EME was much higher in brain and plasma of females. The influence of gonadal hormones on COC metabolite patterns were determined using gonadecto-mized and prepubertal rats. Castration of male or female rats did not alter brain or plasma COG, but did decrease BE concentrations. Seven-day-old pups injected with 15 mg/kg of COC had higher blood and brain COC than adults and relatively low levels of metabolites. No sex differences were found for COG, BE, or EME in brain or plasma of pups. These findings indicate that although gonadal steroids influence COC metabolism, these effects do not explain sex differences in COC-induced behaviors.

关键词：脑/代谢可卡因/类似物和衍生物可卡因/血液可卡因/代谢动力学运动活动/药物作用麻醉品/血液麻醉品/代谢睾丸切除术卵巢切除术大鼠 Sprague-Dawley 性征动物女(雌)性男(雄)性大鼠

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Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第13期9卷 1831-1836页

作者： Kozikowski, AP Simoni, D Roberti, M Rondanin, R Wang, SM Du, PF Johnson, KM Georgetown Univ Med Ctr Drug Discovery Program Inst Cognit & Computat Sci Washington DC 20007 USA Dipartimento Sci Farmaceut I-44100 Ferrara Italy Dipartimento Sci Farmaceut I-40126 Bologna Italy Univ Texas Med Branch Dept Pharmacol & Toxicol Galveston TX 77555 USA

In order to further explore the importance of cocaine's bridge nitrogen atom in binding to the dopamine transporter (DAT). we have synthesized the previously known racemic 8-oxa-norcocaines 3-6 in which the nitrogen atom has been replaced by oxygen. Additionally, to avoid incorrect interpretations of biological data that may stem from the use of racemic materials, several of these analogues were synthesized and tested in non-racemic form. (-)-8-Oxa-norcocaine (3) was found to bind to the cocaine recognition site and to inhibit the dopamine transporter with potencies only about 8-fold and 4-fold, respectively, less than those of norcocaine (2). (-)-8-Oxa-pseudonorcocaine (4) as well as (+)-8-oxa-norcocaine (3) were found to be comparable in activity to (-)-oxa-norcocaine. These pharmacological findings support our earlier suggestion that cocaine is likely to bind in its neutral form to the DAT. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：载体蛋白质类/代谢可卡因/类似物和衍生物可卡因/化学合成可卡因/化学可卡因/药理学多巴胺/代谢多巴胺质膜转运蛋白质类多巴胺摄取抑制剂/代谢动力学马吲哚/代谢膜糖蛋白类膜转运蛋白质类神经组织蛋白质类立体异构现象

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Monitoring cocaine use in substance-abuse-treatment patients by sweat and urine testing

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JOURNAL OF ANALYTICAL TOXICOLOGY 1999年第5期23卷 313-322页

作者： Preston, KL Huestis, MA Wong, CJ Umbricht, A Goldberger, BA Cone, EJ Natl Inst Drug Abuse Intramural Res Program Baltimore MD 21224 USA Univ Vermont Dept Psychol Burlington VT 05405 USA Univ Florida Coll Med Dept Pathol Immunol & Lab Med Gainesville FL USA

Sweat and urine specimens were collected from 44 methadone-maintenance patients to evaluate the use of sweat testing to monitor cocaine use. Paired sweat patches that were applied and removed weekly (on Tuesdays) were compared with 3–5 consecutive urine specimens collected Mondays, Wednesdays, and Fridays. All patches (N = 930) were extracted in 2.5 m/of solvent and analyzed by ELISA immunoassay (cutoff concentration 10 ng/mL); a subset of patches (N = 591) was also analyzed by gas chromatography-mass spectrometry (GC-MS) for cocaine, benzoylecgonine (BZE), and ecgonine methyl ester (EME) (cutoff concentration 5 ng/mL). Urine specimens were subjected to qualitative analysis by EMIT (cutoff 300 ng/mL) and subsets were analyzed by TDx (semiquantitative, LOD 30 ng/mL) and by GC-MS for cocaine (LOD 5 ng/mL). Results were evaluated to (1) determine the relative amounts of cocaine and its metabolites in sweat; (2) assess replicability in duplicate patches; (3) compare ELISA and GC-MS results for cocaine in sweat; and (4) compare the detection of cocaine use by sweat and urine testing. Cocaine was detected by GC-MS in 99% of ELISA-positive sweat patches; median concentrations of cocaine, BZE, and EME were 378, 78.7, and 74 ng/mL, respectively. Agreement in duplicate patches was approximately 90% by ELISA analysis. The sensitivity, specificity, and efficiency of sweat ELISA cocaine results as compared with sweat GC-MS results were 93.6%, 91.3%, and 93.2%, respectively. The sensitivity, specificity, and efficiency between ELISA sweat patch and EMIT urine results were 97.6%, 60.5%, and 77.7%, respectively. These results support the use of sweat patches for monitoring cocaine use, though further evaluation is needed. ? Previous | Next Article ?Table of Contents This Article J Anal Toxicol (1999) 23 (5): 313-322. doi: 10.1093/jat/23.5.313? Free Full Text (PDF)Free Classifications ArticlesServices Alert me when cited Alert me if corrected Find similar articles Similar arti

关键词：可卡因/类似物和衍生物可卡因/分析可卡因/尿可卡因相关性障碍/药物疗法可卡因相关性障碍/尿酶多种免疫测定技术酶联免疫吸附测定评价研究气相色谱-质谱法美沙酮/治疗应用可重复性结果敏感性与特异性物质滥用检测/方法汗/化学青少年成年人老年人女(雌)性人类男(雄)性中年人

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