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1.
The synthesis and a preliminary biological characterization of a new class of N-benzyl-aminoalcohols which have serotonin (5-HT2) and dopamine (D2) receptor affinity is described. In vitro competition binding studies were conducted with the new molecules and 3H-spiperone on crude membrane preparation from rat striatum and frontal cortex. One of these compounds, 3-benzylamino-1-(4-fluoro-2-iodophenyl)-propan-1-ol (6f), whose IC50 values are in the micromolar range for both the D2 and 5-HT2 receptors, was prepared in iodine-125 labelled form (6i) by nucleophilic substitution of the bromine atom of 3-benzylamino-1-(2-bromo-4-fluorophenyl)-propan-1-ol (6d). In the in vivo studies, conducted on rats, the radiolabelled molecule 6i shows a good capacity to cross the blood–brain barrier (BBB) with a mean value of first pass cerebral extraction (E) of ca. 50% when the regional cerebral blood flow, measured with microsphere technique, is in the experimental animal's physiologic range (0.8–1 mL/min/g). A preliminary in vitro autoradiographic distribution on coronal rat brain slices of the radioiodinated molecule showed that it was preferentially localized in the striatum and in the cerebral regions rich in dopamine- and serotonin receptors, even if a high non-specific binding was observed.  相似文献   

2.
Iodobenzamide is a promising agent to investigate D2 receptors by SPECT in living human brain. In this work, we have evaluated this radiolabeled compound in two animal models of D2 receptors supersensitivity. In the first model, rats were treated chronically with haloperidol during three weeks (S.C. injection of 0.5 mg/kg/day). One week after the last day of treatment, they were I.V. injected with 125I-IBZM. In vivo specific binding study showed a 45 percent increase of 125I-IBZM fixation in the striatum of treated rats. In a second step of experiments, animals were unilaterally lesioned by a stereotaxic injection of 6-OHDA in the substantia nigra, 23 days before receiving 125I-IBZM. Autoradiographic analysis of coronal brain sections showed a 38 percent enhancement of 125I-IBZM in vivo binding in the striatum on the lesioned side as compared to the contralateral intact side; this increase occurred in striatal lateral area. These data demonstrate that 125I-IBZM is convenient to detect alterations of dopamine D2 receptors in vivo in the rat. Thus IBZM labelled with 123I can be a very useful imaging agent for the exploration of D2 receptors in pathological situations.  相似文献   

3.
In vivo dopamine receptor binding of the newly synthesized ligand, 125I-2'-iodospiperone (125I-2'-ISP), was studied in mouse brain. The highest accumulation was found in the striatum. Analysis of the striatal homogenate showed the 125I-2'-ISP to be metabolically stable. Furthermore, this striatal binding was saturable and displaced only by dopaminergic drugs. On the other hand, the accumulation in the cortex was as low as that of the cerebellum and uneffected by the administration of serotoninergic drugs and dopaminergic drugs; results assessed by macroautoradiographic studies. Thus, the newly synthesized 125I-2'-ISP presented high affinity for dopamine receptors in vivo and therefore, holds great potential for the in vivo dopamine receptor studies, provided 123I becomes readily available.  相似文献   

4.
A new dopamine transporter (DAT) ligand, (E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4′-methyl-phenyl) nortropane (FE-PE2I, 6), derived from PE2I (1), was prepared and found to be a potent inhibitor of rodent DAT in vitro. Compound 6 was radiolabelled with fluorine-18 (t1/2 = 109.8 min) for PET studies in monkeys. In vivo PET measurements showed a regional distribution in brain that corresponds to the known distribution of DAT. This binding was specific, reversible and the kinetics of [18F]6 binding in brain were faster than for its lead compound, [11C]1. The possible presence of a hydroxymethyl-radiometabolite formed by oxidation in the 3β-benzylic position of [18F]6 warrants further detailed evaluation of the metabolism of [18F]6. [18F]6 is a potential radioligand for imaging DATs in the human brain with PET.  相似文献   

5.
Cytotoxic actions of various prostaglandins were examined on L1210 mouse leukemia and several human leukemia cell lines, and prostaglandin D2 (PGD2) was found most active. PGD2 exerted a dose dependent inhibition of L1210 cell growth over 3.6 μM. At 14.3 μM growth was completely inhibited, and the number of viable cells remarkably decreased during culture. Microscopically the remaining cells showed degenerative changes with many vacuoles in their cytoplasm. The IC50 value of PGD2 on L1210 cell growth was calculated to be 6.9 μM (2.4 μg/ml), and at this concentration the DNA synthesis in 24 hr cultured cells was also decreased to a half of the level in the control cells. Such growth inhibition by PGD2 was also found at similar concentrations with several human leukemia cell lines such as NALL-1, RPMI-8226, RPMI-8402, and Sk-Ly-16. Among other prostaglandins tested, PGA2 showed a comparable, and PGE2 a less but significant growth inhibitory activity, while PGB2, PGF and PGI2 had no such effects on cell proliferation at 14.3 μM concentration. These results suggest a potential antineoplastic activity of PGD2.  相似文献   

6.
The biochemical properties of central nervous system (CNS) dopamine (DA) D1 and D2 receptors were examined using the specific antagonists [3H]SCH23390 and [3H]raclopride, respectively. There is a different participation of sulfhydryl (-SH) and disulfide (-SS-) groups in the binding site and/or coupling to second messenger systems of D1 and D2 receptors. The ionic studies with [3H]SCH23390 showed slight agonist and antagonist affinity shifts for the D1 receptor. On the other hand, the D2 receptor is very sensitive to cations; even if lithium and sodium influence specific [3H]raclopride binding in a similar manner, there appear to be quantitative differences between these two ions that cannot be explained by surface charge mechanisms. The distribution of D1 and D2 receptors was heterogenous in both species, with the greatest densities in the neostriatum, where the highest concentrations of DA and metabolites were measured. Regions with low endogenous DA content (cerebral cortex and hippocampus) had lower densities of DA receptors. Furthermore, these binding sites were differentially localized within the various regions, and there were substantially more D1 than D2 receptors. The functional significance and heterogeneities in the distribution of D1 and D2 receptors can be related to dopaminergic innervation and turnover.  相似文献   

7.
125I-Spiperone binds with high affinity (KD 0.3 nM) to a single specific site (Bmax 34 pmol/g wet weight) in homogenates of rat corpus striatum. Specific binding is about 40-60 percent of total binding and is displaced stereo-specifically by butaclamol and clopenthixol. Neuroleptic drugs of various classes are potent inhibitors of 125I-spiperone binding (Ki's 1-10 nM). Selective dopamine antagonists such as sulpiride (Ki 50 nM) and dopamine agonists such as apomorphine (Ki 200 nM) are also potent inhibitors. The drug specificity of 125I-spiperone binding correlates well with that of 3H-spiperone binding, providing good evidence that 125I-spiperone labels D2 dopamine receptors in striatal membranes. 125I-Spiperone, with its high specific activity (2200 Ci/mmol) may prove to be a useful ligand in studies examining D2 dopamine receptors in soluble preparations and by autoradiography. Furthermore iodinated spiperone may be useful in radioreceptor assays of neuroleptic drug levels and, in a 123I-labeled form, for imaging of dopamine receptors, in vivo, using single photon tomography.  相似文献   

8.
The cyclohexyl piperazine 1 (1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-propyl]-piperazine) has been shown to be a potent and selective sigma-2 receptor ligand. In the present study, we prepared [(11)C]1 by O-alkylation of the phenolic precursor 2 with [(11)C]CH(3)I. [(11)C]1 was obtained in a 29% non-decay corrected yield and specific activity of 9299 mCi/micromol calculated at end-of-synthesis. The biodistribution of [(11)C]1 in mouse brain demonstrated rapid and homogenous concentration in all brain structures, which included the cortex, thalamus, cerebellum and striatum. Co-administration of unlabelled 1 (1 mg/kg) or the sigma-2 selective ligand SM-21 (1 mg/kg) failed to show any significant inhibition of [(11)C]1 uptake in the mouse brain. The evaluation of this radioligand in vivo in the mouse clearly indicates that it does not possess the required properties for studying sigma-2 receptors in the brain using PET.  相似文献   

9.
D(2)-like antagonists potentiate dopamine release. They also inhibit dopamine uptake by a mechanism yet to be clarified. Here, we monitored dopamine uptake in the striatum of anesthetized mice. The dopamine overflow was evoked by brief electrical stimulation of the medial forebrain bundle (four pulses at 100 Hz) and was monitored with carbon fiber electrodes combined with continuous amperometry. The decay phase of evoked overflows reflects dopamine half-life, which entirely depends on uptake. The D(2)-like antagonists haloperidol and eticlopride enhanced the half-life by 45% and 48%, respectively, a moderate effect as compared to the uptake blocker nomifensine (528%). Both D(2)-like antagonists did not affect dopamine uptake in mice lacking D(2) receptors. Inhibition of tonic dopamine release by gamma-butyrolactone did not mimic the enhancing effect of D(2) antagonists on dopamine half-life. However, prolonged stimulation boosted dopamine uptake and this effect was not observed after haloperidol treatment or in mice lacking D(2) receptors. Therefore, dopamine uptake is accelerated in conditions of excessive D(2) stimulation but not finely tuned in resting conditions. Inhibition of dopamine uptake by D(2) antagonists synergizes with the potentiation of dopamine release to strongly alter the phasic dopamine signaling.  相似文献   

10.
Pergolide is a potent, direct-acting dopamine agonist used in treating Parkinson's disease. It is an agonist found recently to have high affinity for D3 receptors. The affinity of pergolide for D1 receptors is lower than for D2 receptors, and there have been some reports that it may not interact with D1 receptors in vivo at doses used to activate D2 receptors. A growing body of evidence suggests that pergolide does occupy and activate D1 receptors in vivo, although the relevance to therapeutic efficacy in Parkinson's disease needs further study.  相似文献   

11.
D2 and D3 dopamine receptors belong to the superfamily of G protein-coupled receptors; they share a high degree of homology and are structurally similar. However, they differ from each other in their second messenger coupling properties. Previously, we have studied the differential coupling of these receptors to G proteins and found that while D2 receptor couples only to inhibitory G proteins, D3 receptor couples also to a stimulatory G protein, Gs. We aimed to investigate the molecular basis of these differences and to determine which domains in the receptor control its coupling to G proteins. For this purpose four chimeras were constructed, each composed of different segments of the original D2 and D3 receptors. We have demonstrated that chimeras with a third cytoplasmic loop of D2 receptor couple to Gi protein in a pattern characteristic of D2 receptor. On the other hand chimeras containing a third cytoplasmic loop of D3 receptor have coupling characteristics like those of D3 receptor, and they couple also to Gs protein. These findings demonstrate that the third cytoplasmic loop determines and accounts for the coupling of dopamine receptors D2 and D3 to G proteins.  相似文献   

12.
A high striatum: cerebellum ratio of 77Br-p-bromospiperone (77Br-BrSp) was observed in rat brain following tail vein injection of the drug. Striatal 77Br-BrSp was stereospecifically displaced by the isomers of flupenthixol. After chronic haloperidol administration striatal dopamine receptor supersensitivity was demonstrated both by increased 3H-spiperone binding to striatal membranes in vitro and by increased striatal 77Br-BrSp content. These results confirm and extend previous findings and enhance interest in the use of 77Br-BrSp for the in vivo assessment of central dopamine receptors in man.  相似文献   

13.
Antagonistic and reciprocal interactions are known to exist between adenosine and dopamine receptors in the striatum. In the present study, double immunofluorescence experiments with confocal laser microscopy showed a high degree of colocalization of adenosine A(2A) receptors (A(2A)R) and dopamine D(2) receptors (D(2)R) in cell membranes of SH-SY5Y human neuroblastoma cells stably transfected with human D(2)R and in cultured striatal cells. A(2A)R/D(2)R heteromeric complexes were demonstrated in coimmunoprecipitation experiments in membrane preparations from D(2)R-transfected SH-SY5Y cells and from mouse fibroblast Ltk(-) cells stably transfected with human D(2)R (long form) and transiently cotransfected with the A(2A)R double-tagged with hemagglutinin. Long term exposure to A(2A)R and D(2)R agonists in D(2)R-cotransfected SH-SY5Y cells resulted in coaggregation, cointernalization and codesensitization of A(2A)R and D(2)R. These results give a molecular basis for adenosine-dopamine antagonism at the membrane level and have implications for treatment of Parkinson's disease and schizophrenia, in which D(2)R are involved.  相似文献   

14.
Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.  相似文献   

15.
16.
Relatively selective dopamine receptor agonists, like bromocriptine, lergotrile, pergolide and N,N-di-n-propyl-dopamine, lower arterial pressure in conscious spontaneously hypertensive rats and in several anesthetized animal preparations. This effect has been attributed to stimulation of dopamine receptors since it can be specifically antagonized by several dopamine receptor blocking agents (domperidone, haloperidol, pimozide, sulpiride). The two main mechanisms which can theoretically intervene in the antihypertensive effects of dopamine agonists are direct smooth muscle relaxation mediated by stimulation of post junctional DA1-dopamine receptors and the reduction of the neural release of norepinephrine resulting from activation of of DA2-dopamine receptors on ganglionic bodies or sympathetic nerve terminals. Other accessory mechanisms of undoubted interest might be a natriuretic effect or a decrease of aldosterone release. On the basis of the presently available pharmacological results in experimental animals, it is not unreasonable to advance the hypothesis that agonists of DA1- and DA2-dopamine receptors produce cardiovascular changes most compatible with an antihypertensive activity being due to a fall in peripheral resistance. However, before any of these compounds can become of therapeutic interest further research in this field is necessary to explore whether it is possible to minimize or even entirely avoid certain unwanted effects (vomiting, nausea, endocrinological alterations) that appear to be intimately associated particularly with those agents stimulating the DA2-dopamine receptors subtype. A more thorough pharmacological characterization of human dopamine receptors would be useful to provide an insight into whether novel chemical approaches can solve some of these problems. Finally, the ideal profits of future dopamine receptor agonists aimed at the treatment of elevated arterial pressure is discussed.  相似文献   

17.
A new type of dendritic molecules Gd-DTPA-XDA-D1-Glc(OH), which work as a functionalized ligand coordinating gadolinium(III) ion at the center of their frameworks with two glucose moieties on the molecular surfaces, were readily synthesized with high yield. The structures were established by IR, 1H, 13C NMR, and mass spectral studies. Its bio-distribution patterns were evaluated on rats.  相似文献   

18.
In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptors, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either drug alone given. Since it has been suggested that dopamine receptors, among others, may play a role in anti-immobility effect of IMI, in the present study we examined the effect of AMA (10 mg/kg) and IMI (5 and 10 mg/kg) given separately or jointly, as a single dose or repeatedly (twice daily for 14 days) on the dopamine D2 and D3 receptors in the rat brain, using receptor autoradiography. Following repeated administration of AMA alone or given in combination with IMI (5 mg/kg), the binding of [3H]quinpirole (dopamine D2/D3 receptors agonist) was increased, and similar changes were observed at the level of mRNA encoding dopamine D2 receptors. We used [3H]7-OH-DPAT to selectively label the dopamine D3 receptors. This experiment has shown that AMA given repeatedly did not induce statistically significant changes in the D3 receptor binding, while IMI at both used doses, increased the [3H]7-OH-DPAT binding, and this effect was still observed after repeated joint administration of AMA with both doses of IMI. However, using both radioligands, we did not observe any synergistic or even additive effects in the binding studies after joint administration of AMA and IMI. Nevertheless, we can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain, and this effect may explain their synergistic action observed in the behavioral studies involving dopaminergic transmission.  相似文献   

19.
A series of new 1,4-disubstituted triazoles was prepared from appropriate arylacetylenes and aminoalkylazides using click chemistry methodology. These compounds were evaluated as potential ligands on several subtypes of dopamine receptors in in vitro competition assays, showing high affinity for dopamine D3 receptors, lower affinity for D2 and D4, and no affinity for the D1 receptors. Compound 18 displayed the highest affinity at the D3 receptor with a Ki value of 2.7 nM, selectivity over D2 (70-fold) and D4 (200-fold), and behaviour as a competitive antagonist in the low nanomolar range.  相似文献   

20.
Ja-Hyun Baik 《BMB reports》2013,46(11):519-526
Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA signaling in mesolimbic neurotransmission are widely believed to modify reward-related behaviors and are therefore closely associated with drug addiction. Recent evidence now suggests that as with drug addiction, obesity with compulsive eating behaviors involves reward circuitry of the brain, particularly the circuitry involving dopaminergic neural substrates. Increasing amounts of data from human imaging studies, together with genetic analysis, have demonstrated that obese people and drug addicts tend to show altered expression of DA D2 receptors in specific brain areas, and that similar brain areas are activated by food-related and drug-related cues. This review focuses on the functions of the DA system, with specific focus on the physiological interpretation and the role of DA D2 receptor signaling in food addiction. [BMB Reports 2013; 46(11): 519-526]  相似文献   

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