Dopamine receptor stimulants N-0923 and (+/-)-<Emphasis Type="Italic">threo-</Emphasis>methylphenidate: Labeling with tritium

Summary Dopamine receptor ligands N-0923 (1) and (+/-)-threo-methylphenidate (4) have been labeled with tritium at high specific activity, for becoming useful tools to study the dopamine receptor family.     

The Electronic Structure of Dopamine. An ab initio Electrostatic Potential Study of the Catechol Moiety

Electronic properties of dopamine were studied by the ab initio STO-3G MO method. The molecular electrostatic potential (MEP) around the aromatic ring and the catechol group remains practically the same in 3,4-dihydroxytoluene (a model compound) and in neutral dopamine examined in its two extended conformations, namely that found in the crystal (side-chain and aromatic ring almost perpendicular) and the one corresponding to 2-amino-6,7-dihydroxytetralin (6,7-ADTN) (side-chain and aromatic ring almost coplanar). In protonated dopamine and in dopamine hydrochloride, the electrostatic potential of the catechol moiety is overshadowed by the positive charge, but the main features remain discernible. The catechol moiety was examined in its two coplanar conformations containing a ‘flip-flop H-bond’. The electrostatic potential around the catechol moiety is quite complex, with alternating positive and negative maxima. At increasing distances above and away from the catechol moiety, only two peripheral maxima, one negative and one positive, remain perceptible. The ‘flip-flop’ mechanism results in an approximate interchange of these two potential maxima, a fact which tends to level out the structural differences between the α- and β-rotamer of dopamine. Based on these results and on the structure of rigid agonists, some pharmacophoric features of dopamine agonists are proposed.     

Synthesis and biological evaluation of 1-(4-(4-(4-[18F]fluorobenzyl)-1-piperazinyl)butyl)indolin-2-one as dopamine D4 receptor ligand

A potential dopamine D₄ receptor ligand, 1-(4-(4-(4-fluorobenzyl)-1-piperazinyl)butyl)indolin-2-one (4) was synthesized through a four-step process and its affinity and selectivity for dopamine D₂-like receptors was determined through in vitro receptor binding assay. [¹⁸F]4 was prepared using a one-pot two-step method with total radiochemical yield 21.2 % (decay-corrected). The molar radioactivity was around 135 GBq/μmol and the radiochemical purity was greater than 95.5 %. The partition coefficient (Log P) of [¹⁸F]4 was determined to be 2.10 ± 0.30 through octanol experiment. The in vivo biodistribution and the competitive distribution of [¹⁸F]4 in rat exposed that the tracer passes through blood–brain-barrier (BBB) and may specifically bind to D₄ receptor. Metabolite analysis revealed that there was no metabolism of [¹⁸F]4 in brain. Conclusively, these preliminary results demonstrated that [¹⁸F]4 shows promises as a radioligand for the in vivo study of dopamine D₄ receptor.     

Synthesis of 2-substituted (+/-)-(2r,3r,5r)-tetrahydrofuran-3,5-dicarboxylic acid derivatives

An efficient synthesis of 2-substituted (+/-)-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid derivatives has been developed. Starting from 5-norborne-2-ol, the key intermediate (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) was synthesized in an efficient six-step sequence. The key transformation is the base-catalyzed methanolysis-rearrangement of (+/-)-6,7-exo,exo-(isopropylidenedioxy)-4-exo-iodo-2-oxabicyclo[3.2.1]octan-3-one (14). Further manipulation of the 3-substituent of (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) followed by deprotection of the diol moiety and ring opening catalyzed by RuCl(3)/NaIO(4) gave the title compounds in good yield.     

Synthesis and spectral properties of 6,7-dimethoxy-1-[(ortho; and para-R)-phenyl]-3,4-dihydroisoquinoline

The preparation of eleven novel 6,7-dimethoxy-1-[(ortho, and para-R)-phenyl]-3,4-dihydroisoquinolines with possible pharmacological activity is described. The structure of all products was corroborated by ir, ¹H-nmr, ¹³C-nmr, and ms.     

Synthesis and characterization of novel α- or β-tetra[6,7-dihexyloxy-3-(4-oxyphenyl)coumarin]-substituted metal-free and metallo phthalocyanines

The synthesis of novel phthalonitriles substituted at 3- or 4-position with 6,7-dihexyloxy-3-(4-oxyphenyl)coumarin were performed. The metal-free and metallo phthalocyanines (MPcs) (M = Zn, Co, Cu) were prepared by cyclotetramerization of 6,7-dihexyloxy-3-[p-(2′,3′-dicyanophenoxy)phenyl]coumarin or 6,7-dihexyloxy-3-[p-(3′,4′-dicyanophenoxy)phenyl]coumarin. The newly prepared compounds, phthalonitriles and Pcs, have been characterized by elemental analysis, ¹H NMR, ¹³C NMR, MALDI-TOF, IR, UV–Vis and fluorescence spectral data. The electronic spectra exhibit bands of coumarin identity along with characteristic Q and B bands of the Pc core. The IR-spectra of all Pcs showed three characteristic intense bands at 1709–1700 cm⁻¹ for lactone carbonyl, two bands at 1489–1604 cm⁻¹ for conjugated olefinic system.     

Serotonin receptor agonists buspirone and (+/−)-DOB: Tritiation at high specific activity

Serotonergic agonists buspirone 1 and (+/–)-DOB 4 have been labeled with tritium at high specific activity and have emerged as valuable tools to study the serotonin receptor family.This revised version was published online in November 2005 with corrections to the Cover Date.     

A novel resonance Rayleigh scattering aptasensor for dopamine detection based on an Exonuclease III assisted signal amplification by G - quadruplex nanowires formation

A new method was constructed for detecting dopamine based on aptamer-specific recognition and resonance Rayleigh scattering (RRS) of G - quadruplex nanowires (G - wires). The dopamine aptamer was used to recognize the target of dopamine, and the Exonuclease III was applied to cleave the hairpin DNA, and the G - wire formation was induced in the presence of K⁺ and Mg²⁺. This phenomenon was confirmed by polyacrylamide gel electrophoresis. Thus, a quantitative relationship between the RRS intensity of the G - wires and the dopamine concentration was established. The experimental conditions were optimized, such as the concentration of Mg²⁺, reaction temperature, reaction time and the concentration of Exonuclease III in the reaction system, and the interference substances were investigated, such as uric acid, ascorbic acid and serotonin. Under the optimal conditions, there was a good linear relationship between the RRS and the logarithm of dopamine concentration in the range from 5.0 × 10^-11 M to 1.0 × 10^-8 M (r = 0.995), with a detection limit of 1.2 × 10^-11 M. The novel method for dopamine detection showed excellent selectivity and high sensitivity, and could be used to detect dopamine in mice brain tissues.     

Synthesis and X-ray diffraction study of 5-(8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-1,3-dimethylbarbituric acid

The reaction of cotarnine with 1,3-dimethylbarbituric acid afforded 5-(8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-1,3-dimethylbarbituric acid. Its crystal structure was established by X-ray diffraction analysis and the structure in solution was studied by ¹H NMR spectroscopy. This compound has a zwitterionic structure. In the crystal, the molecules are linked in dimers by intermolecular hydrogen bonds, and in solutions, the dimers occur in equilibrium with the monomers.     

(±)-6,7-丙酮缩二醇-3-酮-庚酸乙酯合成研究

用对甲苯磺酸-2,3-丙酮缩甘油酯(2)与乙酰乙酸乙酯盐、碳酸二乙酯反应, 制备β-酮酯类衍生物1. 以(±)-1,2-丙酮缩甘油为起始物, 经对甲苯磺酰化、亲核取代、脱羧等反应, 方便、高产率地合成了6,7-丙酮缩二醇-3-酮-庚酸乙酯(1). 试图通过对甲苯磺酸-2,3-丙酮缩甘油酯(2)和乙酰乙酸乙酯双阴离子反应制备6,7-丙酮缩二醇-3-酮-庚酸乙酯(1)未获成功. 所合成的化合物经元素分析, IR, ¹H NMR, ¹³C NMR和MS光谱表征.     

Tritium labeling of opiate receptor ligands lofentanil and (-)-bremazocine

Summary Opiate receptor ligands lofentanil 1 and (-)-bremazocine 4 have been labeled with tritium at high specific activity, becoming useful tools to study subclasses of the opiate receptor family.     

Tritium concentration in fresh,brackish and sea-water samples in Rokkasho-Village,Japan, bordered by nuclear fuel cycle facilities

Summary In order to identify the concentration of tritium (³H) in areas of fresh, brackish and sea water, bordered by nuclear fuel facilities at Rokkasho-Village, Aomori, Japan, water samples were collected from 2001 to 2004 at six points in those areas. Concentration ranges of tritium in fresh river water, brackish lake and seawater samples were 0.60 to 1.1 Bq^. l^-1(mean value 0.79 Bq^. l^-1), 0.20 to 0.87 Bq^. l^-1(mean value 0.41 Bq^. l^-1), and 0.08 to 0.25 Bq^. l^-1(mean value 0.15 Bq^. l^-1), respectively. Relationships between tritium concentrations and salinity in the samples showed a clear negative correlation. Moreover, the seasonal variation of tritium in water from Rokkasho-Village was high in spring and low in fall.     

Association between monthly-reported rhinitis by children from basic schools and monthly-averaged air pollutants,at Lisbon (Portugal)

3-(4-[¹⁸F]fluorobenzyl)-8-hydroxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one ([¹⁸F]FHTP) was in vitro and in vivo evaluated as a putative dopamine D₄ receptor radioligand. Its inhibition constant (K _i ) for cloned human dopamine D_4.2 receptor was determined to be 2.9 nM and it displayed a 2000-fold D₄-selectivity over the D_2long subtype. Its partition coefficient (logP) was measured to be 1.11. Biodistribution, blocking distribution and metabolism studies in rats demonstrated that the specific distribution of [¹⁸F]FHTP in brain regions, suggesting that [¹⁸F]FHTP may be a suitable PET imaging agent for in vivo studies of the dopamine D₄ receptor.     

Determination of Dopamine Using 2-(4-Boronophenyl)quinoline-4-carboxylic Acids as Fluorescent Probes

The selective identification of dopamine is a significant issue because this compound is an important neurotransmitter closely related to Parkinson’s disease and other mental disorders. 2-(4-Boronophenyl)quinoline-4-carboxylic acid (PBAQA) has been previously reported as a water-soluble fluorescent probe for catechol. However, there are no significant differences in the binding constants between catechol and catecholamines, such as dopamine or levodopa. Here a series of bis-boronic acid compounds based on PBAQA were synthesized and the binding activities were characterized. As a representative compound, the binding constant of 4-(4-((3-(3-borono-4-chlorobenzamido)propyl)carbamoyl)quinolin-2-yl)boronic acid to dopamine is up to 10⁴?L?mol^?1 and much higher than previously reported boronic acid probes. Dopamine selectivity may be achieved by the variation of the substituents in the probe molecules. 4-(4-((3-(3-Borono-4-methoxybenzamido)propyl)carbamoyl)quinolin-2-yl)boronic acid has a stronger binding affinity to dopamine (K_a=5204?±?106?L?mol^?1) than catechol (K_a=2588?±?273?L?mol^?1) or levodopa (K_a=2383?±?273?L?mol^?1). This fluorescence response was used for determining dopamine in a range from 5?×?10^?5?mol?L^?1 to 5?×?10^?4?mol?L^?1 with a detection limit of 7.7?×?10^?6?mol?L^?1. This compound has been successfully used for the assay of dopamine in rabbit plasma, exhibiting excellent specificity. It is believed that synthesized compounds hold great promise as practical platforms to monitor dopamine levels.     

Stereoselective synthesis of and atropisomerism in 4-pyridyl-3-(1-pyridinio)-3,4-trans-1,2,3,4-tetrahydropyridines and their transformation products

A series of 2-oxo-4-pyridyl-3-(1-pyridinio)-5-cyano-3,4-trans-1,2,3,4-tetrahydropyridine-6-6-olates were prepared by condensation of pyridinium ylides with α,β-unsaturated carbonyl compounds or more conveniently by a three-component condensation of pyridinium ylides, pyridine aldehydes, and ethyl cyanoacetate 3 and/or 6 . This analogues of the above tetrahydropyridines were prepared in a similar way starting from suitable substrates. Spectroscopic data revealed that the reaction leads to trans-isomers around the C³-C⁴ bond and is atroposelective. The conformation of and tautomerism in the tetrahydropyridines are discussed in the light of ¹H NMR data. The reaction of 5-cyano-3-(3-methyl-1-pyridinio)-2-oxo-4-(3-pyridyl)-1,2,3,4-tetrahydropyridine-6-thiolate 10c with phenacyl bromide was found to give 3-hydroxy-5-oxo-7-(3-pyridyl)-6-(3-methyl-1-pyridinio)-3-phenyl-8-cyano-6,7-trans-2,3,6,7-tetrahydrothiazol[3,2a]pyridine bromide, the crystal and molecular structure of which has been determined by X-ray crystallographic analysis.     

A short and unequivocal synthesis of 5-aminotetrazolo[1,5-a]-quinazoline as a tricyclic analogue of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035)

The discovery of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035) as an extremely potent inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor led to the preparation of several fused tricyclic quinazoline analogues. The present paper reports a new tricyclic derivative: 5-(3-bromoanilino)-7,8-dimethoxytetrazolo[1,5-a]quinazoline. This compound was synthesized by two different pathways viaa 1,3-dipolar cycloaddition of an azide at carbon 2 of the quinazoline ring.     

Tritium in surface waters, tap water and in precipitation in Poland during the 1994–1999 period

Concentrations of tritium in environmental waters (precipitation, rivers, lakes, tap water) have been determined using electrolytic enrichment and liquid scintillation counting. In waters of big rivers (the Vistula and the Odra rivers), lakes and tap water the annual average concentrations were similar to each other being from 1.4 to 1.9 Bq·dm^-3. These concentrations were similar to those in the precipitation in which they ranged from 1.7 to 2.2 Bq·dm^-3. The lowest tritium concentrations were found in waters of the Seashore Region rivers (average for 1994–1999 was 1.1 Bq·dm^-3). The tritium concentrations in surface waters and in precipitation are still higher than that of natural level. The data obtained show that tritium concentration in the water of rivers might depend on the size of drainage area. The observed seasonal variations of tritium concentration in the precipitation collected in Warsaw and at the Mount Sniezka indicate the stratospheric source of tritium. It was found that about 30% of tritium deposited with precipitation is removed to the Baltic Sea with river waters.     

Synthesis and Transformation of 4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoline: Spectral Characterization and Anti-cancer Properties of some Novel Quinazoline Derivatives

An efficient and simple method has been reported for the synthesis of 4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoline ( 2 ) as a key compound for further transformation to other novel 6,7-dimethoxy-2-methyl-4-substituted quinazolines. The structure of the synthesized compounds was characterized by spectroscopic methods. The pathway of some unprecedented reactions was proposed. (E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-3-(4-nitrophenyl)prop-2-en-1-one (11) exhibits high in vitro cytotoxicity on three cell lines, Hepatocellular carcinoma (Hep-G2), Human lung carcinoma (LU-1), and Human breast carcinoma (MCF-7) with IC₅₀ of 2.1, 11.6 and 2.2 μM, respectively.     

Spectrofluorimetric method for the determination of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (tofisopam)

The method described is based on the reaction of tofisopam in dimethyl sulphoxide in the presence of an alkali metal hydroxide at 90–100°C to give 1-ethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-naphthol, which shows intensive fluorescence. The method is suitable for the determination of 5 × 10^?8?5 × 10^?5 g ml^?1 of tofisopam.     

Highly regioselective synthesis of trifluoromethyl derivatives of pyrazolo[1,5-a]pyrimidines bearing fused cycloalkane rings using (2-ethoxycycloalkenyl)-2,2,2-trifluoroethanones

8-Trifluoromethyl-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 9-trifluoromethyl-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolines were efficiently generated by condensation of 5(3)-aminopyrazoles with (2-ethoxycycloalkenyl)-2,2,2-trifluoroethanones and isolated in excellent yields. The regiochemistry of the prepared compounds was established by ¹H, ¹³C and ¹⁹F NMR spectroscopy and X-ray diffraction analysis.