共查询到20条相似文献,搜索用时 31 毫秒
1.
Micioni Di Bonaventura MV Cifani C Lambertucci C Volpini R Cristalli G Froldi R Massi M 《Psychopharmacology》2012,219(4):945-957
Rationale
A2A adenosine receptors (A2AARs) have been proposed to be involved in drug addiction; however, preclinical studies about the effects of A2AAR ligands on alcohol consumption have provided inconsistent results. 相似文献2.
Jensen K Johnson LA Jacobson PA Kachler S Kirstein MN Lamba J Klotz KN 《Naunyn-Schmiedeberg's archives of pharmacology》2012,385(5):519-525
Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These
agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they
may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability
of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A1, A2A, A2B, and A3). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A1, A2A, or A3 receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used
to assess the binding to A2B receptors. Clofarabine and cladribine both bound to the A2A receptor with a K
i of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A3 receptor with a K
i of 10 μM, and none of these compounds bound to the A2B receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A1 receptor. In addition, clofarabine, cladribine, and fludarabine were A1 agonists (IC50 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any
of the adenosine receptor subtypes (K
i > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside
analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism
through which fludarabine-associated toxicity occurs. 相似文献
3.
Rationale
There is increasing interest in antipsychotics intended to manage positive symptoms via D2 receptor blockade and improve negative symptoms and cognitive deficits via 5-HT1A activation. Such a strategy reduces side-effects such as the extrapyramidal syndrome (EPS), weight gain, and autonomic disturbance liability. 相似文献4.
Randall PA Nunes EJ Janniere SL Stopper CM Farrar AM Sager TN Baqi Y Hockemeyer J Müller CE Salamone JD 《Psychopharmacology》2011,216(2):173-186
Rationale
Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. 相似文献5.
Rationale
Metabotropic glutamate (mGlu) receptors have been suggested to play a role in neuropsychiatric disorders including schizophrenia, drug abuse, and depression. Because serotonergic hallucinogens increase glutamate release and mGlu receptors modulate the response to serotonin (5-HT)2A activation, the interactions between serotonin 5-HT2A receptors and mGlu receptors may prove to be important for our understanding of these diseases. 相似文献6.
Reimold M Solbach C Noda S Schaefer JE Bartels M Beneke M Machulla HJ Bares R Glaser T Wormstall H 《Psychopharmacology》2007,190(2):241-249
Rationale Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine
D2, D1 and 5-HT2A receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative
symptomatology, which was implicated with flupentixol’s interaction with 5-HT2A and/or D1 receptors.
Objectives To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 ± 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 ± 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 ± 5.5 mg/day).
Materials and methods Each patient underwent two PET scans with 3-N-[11C]methylspiperone (target: frontal 5-HT2A), [11C]SCH23390 (striatal D1) or [11C]raclopride (striatal D2). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls.
Results D2-RO under FLX was between 50% and 70%, indicating an ED50 of about 0.7 ng/ml serum. 5-HT2A and D1-RO was 20 ± 10% and 20 ± 5% (mean, SEM). Under HAL, D1-RO was 14 ± 6% and under RIS not significantly different from zero.
Conclusions We were able to demonstrate a moderate 5-HT2A and D1 occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below
saturation. Therefore, if flupentixol’s efficacy on negative symptoms is based on its interaction with 5-HT2A and/or D1 receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest
that mechanisms other than D1 or 5-HT2A antagonism may contribute to flupentixol’s efficacy on negative symptoms. 相似文献
7.
Rationale
Several studies have investigated the reinforcing effects of food in genetically engineered mice lacking dopamine D2 receptors (DA D2Rs); however, behavioral economic analyses quantifying reinforcement have not been conducted. 相似文献8.
Lladó-Pelfort L Assié MB Newman-Tancredi A Artigas F Celada P 《Psychopharmacology》2012,221(2):261-272
Rationale
F13640 (befiradol) is a novel 5-HT1A receptor agonist with exceptional selectivity vs. other receptors and binding sites. It shows analgesic activity in animal models and is currently developed for human use. 相似文献9.
Rationale
Cocaine-induced changes in D2 receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D3 receptors is less clear.Objectives
To characterize the effects of repeated cocaine administration on the sensitivity of rats to D2- and D3-mediated behaviors, as well as the binding properties of ventral striatal D2-like and D3 receptors.Methods
Pramipexole was used to assess the sensitivity of rats to D3/D2 agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D2-like and D3 receptors (24 h and 42 days) were also evaluated.Results
Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h–42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose–response curve. Cocaine treatment also decreased B max and K d for D2-like receptors and increased D3 receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists.Conclusions
These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D3 and D2 receptors, with enhancements of D3-mediated behavioral effects observed within 72 h and enhancements of D2-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D3 receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.10.
Mariana Pereira Andrew M. Farrar Jörg Hockemeyer Christa E. Müller John D. Salamone Joan I. Morrell 《Psychopharmacology》2011,213(1):69-79
Rationale
Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A2A receptors in striatal areas, including the nucleus accumbens. 相似文献11.
Kattepura K. Dharmappa Riyaz Mohamed Holenarasipura V. Shivaprasad Bannikuppe Sannanaik Vishwanath 《Inflammopharmacology》2010,18(1):25-31
Objectives
Some of the legumes, spices and medicinal herbs rich in genistein are known for their anti-inflammatory properties. Anti-inflammatory property of these herbs is determined by subjecting secretory phospholipase A2 (sPLA2) inhibition, a key enzyme in the inflammatory reactions by genistein. 相似文献12.
Abstract
Three novel 1-benzhydryl-piperazines with xanthine moiety at N4 were synthesized and tested for 5-HT1A and 5-HT2A receptor affinity. One of the compounds showed the highest affinity (58.6 nM) and selectivity (34 times) to 5-HT2A receptor known for this class of compounds. A set of the three new and 31 previously synthesized 1-arylpiperazines with xanthine moiety at N4 was compiled and a QSAR study was performed in order to rationalize the further synthesis. It was found that the 5-HT1A affinity depends on the shape of the molecules (ovality and number of circuits), the distribution of the electron density in the structures (partial charges at piperazine N1 and xanthine N1) and their charge transfer ability (HOMO energy). The 5-HT2A affinity depends on the lipophilicity of the ligands and the distribution of the electron density in the structures (partial charges at piperazine N4 and xanthine O6). The QSAR results are in a good agreement with known pharmacophore models. 相似文献13.
Hodé Y Reimold M Demazières A Reischl G Bayle F Nuss P Hameg A Dib M Macher JP 《Psychopharmacology》2005,180(2):377-384
Rationale Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT2A receptors, which was fourfold higher than its affinity for dopamine D2 receptors (Hameg et al. 2003).Objectives The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian.Methods Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D2 and serotonin 5-HT2A receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [11C]raclopride and [11C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan.Results Cyamemazine induced near saturation of 5-HT2A receptors (RO=62.1–98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D2 receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2–74.9%). The effective plasma level of cyamemazine leading to 50% of D2 receptor occupancy was fourfold higher than that for 5-HT2A receptors. Accordingly, individual 5-HT2A/D2 RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale.Conclusion This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT2A receptors compared to dopamine D2 receptors. In the dose range 37.5–300 mg, levels of dopamine D2 occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects. 相似文献
14.
Rationale and objectives Given that adenosine A2A antagonists appear to be therapeutic in several animal models of Parkinson’s disease (PD), we examined the extent to which
caffeine and selective A2A and A1 antagonists could enhance contralateral forepaw stepping in the unilateral 6-OHDA-lesioned rat.
Materials and methods Following unilateral injections of 12 μg 6-OHDA into the medial forebrain bundle (MFB), frequency of stepping with both front
paws was counted separately as the paws were dragged anteriorally and laterally by a treadmill.
Results The MFB lesions decreased contralateral stepping by 74–83%, and 8 mg/kg 3,4-dihydroxy-l-phenylalanine (L-DOPA) increased contralateral stepping by 25–26%. Caffeine given systemically (15 mg/kg) or into the dorsal
striatum or external globus pallidus (GPE; 20–40 μg) increased contralateral forepaw stepping by 14%, 27%, and 26%, respectively, and enhanced the effect of 8 mg/kg
L-DOPA on stepping. The selective A2A antagonist SCH-58261 (2 mg/kg) also increased stepping by 13% and enhanced the therapeutic effect of L-DOPA, whereas the
selective A2A antagonist 8-cyclopentyltheophylline (3–7 mg/kg) and A1 agonist N
6-cyclopentyladenosine (0.03–0.2 mg/kg) had no effect. None of these drugs appeared to produce dyskinesic effects.
Conclusions In this well-validated animal model of the akinesic effects of PD, caffeine and a selective A2A, but not an A1, antagonist were able to provide both monotherapeutic and adjunctive therapeutic effects. These data are consistent with
the hypothesis that A2A antagonists may be therapeutic in human PD patients and indicate that the dorsal striatum and GPE are critical sites of therapeutic action.
An erratum to this article can be found at 相似文献
15.
Antoniou K Papadopoulou-Daifoti Z Hyphantis T Papathanasiou G Bekris E Marselos M Panlilio L Müller CE Goldberg SR Ferré S 《Psychopharmacology》2005,183(2):154-162
Rationale There is no consensus on the contribution of adenosine A1 and A2A receptor blockade to motor-activating effects of caffeine.Objective Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A1 and A2A receptor antagonists.Methods The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A2A receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A1 receptor agonist N
6-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined.Results The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3.Conclusions The results indicate a predominant role for A1 receptors in the motor-activating effects of acutely administered caffeine. 相似文献
16.
Malika El Yacoubi Catherine Ledent Marc Parmentier Jean Costentin Jean-Marie Vaugeois 《Naunyn-Schmiedeberg's archives of pharmacology》2009,380(3):223-232
The neuromodulator adenosine, acting through activation of four defined metabotropic receptors called A1, A2A, A2B and A3, has been proposed as an endogenous anticonvulsant. Here, the consequences of deleting the adenosine A2A receptor have been examined in different experimental models of epilepsy. A2AR KO mice were not protected against seizures originating from brainstem structures, namely electroshock-induced seizures.
The intensities of seizures induced by pentylenetetrazol or pilocarpine, as well as the percentages of convulsing mice, were
significantly reduced in A2A receptor knockout (A2AR KO) animals. A2AR KO mice exhibited reduced pentylenetetrazol-induced kindled seizures, demonstrating an important role of the A2A receptor in the acquisition of kindling. These data suggest that adenosine stimulating A2A receptors modulates excitatory neurotransmission and exacerbates limbic seizures. It is therefore suggested that adenosine
A2A receptor antagonists might offer protection from some epileptic syndromes. 相似文献
17.
Knight AR Misra A Quirk K Benwell K Revell D Kennett G Bickerdike M 《Naunyn-Schmiedeberg's archives of pharmacology》2004,370(2):114-123
In the present study we compared the affinity of various drugs for the high affinity agonist-preferring binding site of human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors stably expressed in monoclonal mammalian cell lines. To ensure that the agonist-preferring conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([3H]-ketanserin for 5-HT2A receptor and [3H]-mesulergine for 5-HT2B and 5-HT2C receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([125I]-DOI for 5-HT2A receptor binding and [3H]-5-HT for 5-HT2B and 5-HT2C receptor binding). Competition experiments were subsequently conducted against appropriate concentrations of the agonist radiolabels bound to the agonist-preferring subset of receptors in each preparation. These studies confirmed that there are a number of highly selective antagonists available to investigate 5-HT2 receptor subtype function (for example, MDL 100907, RS-127445 and RS-102221 for 5-HT2A, 5-HT2B and 5-HT2C receptors respectively). There remains, however, a lack of highly selective agonists. (–)DOI is potent and moderately selective for 5-HT2A receptors, BW723C86 has poor selectivity for human 5-HT2B receptors, while Org 37684 and VER-3323 display some selectivity for the 5-HT2C receptor. We report for the first time in a single study, the selectivity of numerous serotonergic drugs for 5-HT2 receptors from the same species, in mammalian cell lines and using, exclusively, agonist radiolabels. The results indicate the importance of defining the selectivity of pharmacological tools, which may have been over-estimated in the past, and highlights the need to find more selective agonists to investigate 5-HT2 receptor pharmacology. 相似文献
18.
Rationale
The serotonin (5-HT) 2A receptor is implicated in numerous psychiatric disorders, making it an important, clinically relevant target. Despite the availability of transgenic mouse lines, the native mouse 5-HT2A receptor is not well-characterized. 相似文献19.
Rationale Atypical antipsychotic drugs have been shown to preferentially affect extrastriatal (mesolimbic) D2/D3 receptors over those within the striatum (nigrostriatal). The striatum does not contain exclusively nigrostriatal dopamine
tracts, however. The caudate nucleus and ventral parts of the striatum primarily contain limbic and associative dopamine pathways
more relevant to psychosis.
Objectives We tested the hypothesis that two pharmacologically distinct atypical antipsychotic drugs, amisulpride and risperidone, would
preferentially occupy of D2/D3 dopamine receptors in limbic and associative regions of the striatum.
Methods Eight amisulpride-treated patients, six risperidone-treated patients and six age- and sex-matched healthy controls were recruited.
Dynamic SPET studies were performed after bolus injection of [123I]epidepride. Binding potential (BP) images were generated using a modified Logan method and aligned between subjects. Regions
of interest (ROIs) were placed around head of caudate and putamen bilaterally on an average BP map derived from aligned control
images. These ROIs were then applied user-independently to the BP maps for each subject to calculate BP for head of caudate
and putamen. Mean occupancy of D2/D3 receptors in each ROI was determined by reference to the drug-free healthy volunteer group. Occupancy values for head of
caudate and putamen were compared using paired Student’s t test.
Results D2/D3 receptor occupancy was 42% in caudate and 31% in putamen for risperidone (t=5.9, df=11, p=0.0001) and 51% in caudate and 37% in putamen for amisulpride (t=11.1, df=15, p<0.0001).
Conclusions Amisulpride and risperidone both show selective occupancy for limbic and associative D2/D3 receptors within the striatum. 相似文献
20.