Dopamine/adenosine interactions related to locomotion and tremor in animal models: Possible relevance to parkinsonism

Abstract Adenosine A 2A antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A 2A antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidolinduced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine. Infusions of MSX-3 into the nucleus accumbens core increased locomotion in haloperidol-treated rats, but there were no effects of infusions into the accumbens shell or ventrolateral neostriatum. In contrast, MSX-3 injected into the ventrolateral neostriatum reduced pimozide-induced tremulous jaw movements. Dopamine/adenosine interactions in different striatal subregions are involved in distinct aspects of motor function

Реконструкция котла ПК-38 на Назаровской ГРЭС в г. Назарово Красноярского края

В работе рассматривается реконструкция котла ПК-38, работающего на твердом топливе Назаровского месторождения. Приведены конструктивные характеристики топки и всех поверхностей нагрева, произведен поверочный расчет котельного агрегата.The paper reviews the reconstruction of the PK-38 boiler, which operates on solid fuel at the Nazarovo deposit. The design characteristics of the furnace and all heating surfaces are presented, and the boiler unit is calibrate

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease

Microwave-assisted ring closure reactions: Synthesis of 8-substituted xanthine derivatives and related pyrimido- and diazepinopurinediones

BACKGROUND: Poly-substituted xanthine derivatives are an important class of compounds in medicinal chemistry. Substitution at the 8-position of the purine ring is generally accessible by ring closure of a carboxamido-substituted uracil precursor. Although several procedures to accomplish this synthetic step have been suggested, it still remains difficult in many cases. RESULTS: Ring closure reaction with hexamethyldisilazane was studied under microwave conditions. Reaction times were dramatically reduced by the application of microwaves in the syntheses of the 8-styrylxanthine derivative istradefylline, and in the preparation of 2-substituted pyrimido [1,2,3-cd]purines. Furthermore, the new procedure allowed the preparation of a previously unaccessible diazepino [1,2,3-cd]purine. Yields were generally improved by the new method. The addition of THF as a co-solvent proved to be crucial. CONCLUSION: A new, fast, and efficient ring closure method for the imidazole ring of xanthine derivatives and related tricyclic compounds has been developed. Apart from improving the syntheses of known compounds, some of which are important pharmacological tools or in development as novel drugs, it allows the preparation of 2-substituted diazepino [1,2,3-cd]purines – a new class of tricyclic purine derivatives

Dopamine/adenosine interactions related to locomotion and tremor in animal models: Possible relevance to parkinsonism

Adenosine A2A antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A2A antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidol-induced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine. Infusions of MSX-3 into the nucleus accumbens core increased locomotion in haloperidol-treated rats, but there were no effects of infusions into the accumbens shell or ventrolateral neostriatum. In contrast, MSX-3 injected into the ventrolateral neostriatum reduced pimozide-induced tremulous jaw movements. Dopamine/adenosine interactions in different striatal subregions are involved in distinct aspects of motor function. © 2008 Elsevier Ltd. All rights reserved

Data_Sheet_1_Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity.PDF

<p>Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A₁ and A_2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A₁ ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a K_i value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A_2A AR affinity. The 8-phenethyl derivative 20h was selective for the A_2A AR (K_i 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A₁ and A_2A ARs with equal potency (K_i A₁, 180 nM; A_2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A₁ ARs (K_i 396 nM), A_2A ARs (K_i 1,620 nM), and MAO-B (IC₅₀ 106 nM) with high selectivity vs. the other subtypes (A_2B and A₃ ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease.</p