2,5'-Disubstituted adenosine derivatives: evaluation of selectivity and efficacy for the adenosine A(1), A(2A), and A(3) receptor.

Novel 2,5'-disubstituted adenosine derivatives were synthesized in good overall yields starting from commercially available guanosine. Binding affinities were determined for rat adenosine A(1) and A(2A) receptors and human A(3) receptors. E(max) values were determined for the stimulation or inhibition of cAMP production in CHO cells expressing human adenosine A(2A) (EC(50) values as well) or A(3) receptors, respectively. The compounds displayed affinities in the nanomolar range for both the adenosine A(2A) and A(3) receptor, without substantial preference for either receptor. The derivatives with a 2-(1-hexynyl) group had the highest affinities for both receptors; compound 4 (2-(1-hexynyl)adenosine) had the highest affinity for the adenosine A(2A) receptor with a K(i) value of 6 nM (A(3)/A(2A) selectivity ratio of approximately 3), whereas compound 37 (2-(1-hexynyl)-5'-S-methyl-5'-thioadenosine) had the highest affinity for the adenosine A(3) receptor with a K(i) value of 15 nM (A(2A)/A(3) selectivity ratio of 4). In general, compounds with a relatively small 5'-S-alkyl-5'-thio substituent (methyl-5'-thio) displayed the highest affinities for both the adenosine A(2A) and A(3) receptor; the larger ones (n- or i-propyl-5'-thio) increased the selectivity for the adenosine A(3) receptor. The novel compounds were also evaluated in cAMP assays for their (partial) agonistic behavior. Overall, the disubstituted derivatives behaved as partial agonists for both the adenosine A(2A) and A(3) receptor. The compounds showed somewhat higher intrinsic activities on the adenosine A(2A) receptor than on the A(3) receptor. Compounds 37, 40 and 45, 48, with either a 5'-S-methyl-5'-thio or a 5'-S-i-propyl-5'-thio substituent had the lowest intrinsic activities on the adenosine A(2A) receptor. For the A(3) receptor, compounds 34, 35, 38, 39, and 46, 47, with a 5'-S-ethyl-5'-thio or a 5'-S-n-propyl-5'-thio substituent had the lowest intrinsic activities.     

Human adenosine A(1), A(2A), A(2B), and A(3) receptors expressed in Chinese hamster ovary cells all mediate the phosphorylation of extracellular-regulated kinase 1/2

The known diverse effects of adenosine on mitogenesis may be related to changes in mitogen-activated protein kinases. In this study we therefore compared the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) via the four known human adenosine receptors A(1), A(2A), A(2B), and A(3), stably transfected into Chinese hamster ovary (CHO) cells. The adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA), known to act on all subtypes, had no effect on untransfected CHO cells, but did cause a substantial time- and dose-dependent phosphorylation in CHO cells transfected with each of the receptors. The maximal phosphorylation was highest in A(1) and A(3) receptor-transfected cells, intermediate in A(2A) and low in A(2B) receptor-expressing CHO cells. For all receptors the half-maximal ERK1/2 phosphorylation was observed at 19-115 nM NECA. NECA acting on adenosine A(2B) receptors was much more potent in stimulating ERK1/2 phosphorylation (EC(50) = 19 nM) than cAMP formation (EC(50) = 1.4 microM). Stimulation with the endogenous ligand adenosine resulted in the same pattern of ERK1/2 phosphorylation as NECA. Concentrations of adenosine that occur physiologically caused an increased phosphorylation after 5 min in CHO cells transfected with any one of the four adenosine receptors. Adenosine at levels reached during ischemia (3 microM) induced a more pronounced, but still transient, activation of ERK1/2. In conclusion, this study shows that all the human adenosine receptors transfected into CHO cells are able to activate ERK1/2 at physiologically relevant concentrations of the endogenous agonist.     

中文关键词索引(2011年第25卷)

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Antioxidant properties of some medicinal plants: Prangos ferulacea (Apiaceae), Sedum sempervivoides (Crassulaceae), Malva neglecta (Malvaceae), Cruciata taurica (Rubiaceae), Rosa pimpinellifolia (Rosaceae), Galium verum subsp. verum (Rubiaceae), Urtica dioica (Urticaceae)

Antioxidant and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities, reducing powers and the amount of total phenolic compounds of aqueous and/or methanolic extracts of some medicinal plants used in Eastern Turkey were studied. These plants are Prangos ferulacea (CASIR), Sedum sempervivoides (HOROZ LELESI), Malva neglecta (EBEMGUMECI), Cruciata taurica (SARILIK OTU), Rosa pimpinellifolia (KOYUN GOZU), Galium verum subsp. verum (MADAVUR OTU), Urtica dioica (ISIRGAN). The highest peroxidation inhibitions were shown by aqueous extracts of C. taurica and R. pimpinellifolia (IC(50): 0.00022 mg/l and IC(50): 23 mg/l, respectively). However, the highest DPPH radical scavenging activity, reducing power and the amount of phenolic compounds were shown by R. pimpinellifolia. The lowest antioxidant properties were shown by aqueous extract of M. neglecta.     

Liquid–air partition coefficients of 1,1‐difluoroethane (HFC152a), 1,1,1‐trifluoroethane (HFC143a), 1,1,1,2‐tetrafluoroethane (HFC134a), 1,1,1,2,2‐pentafluoroethane (HFC125) and 1,1,1,3,3‐pentafluoropropane (HFC245fa)

Blood–air and tissue–blood coefficients (λ) are essential to characterize the uptake and disposition of volatile substances, e.g. by physiologically based pharmacokinetic (PBPK) modelling. Highly volatile chemicals, including many hydrofluorocarbons (HFC) have low solubility in liquid media. These characteristics pose challenges for determining λ values. A modified head‐space vial equilibrium method was used to determine λ values for five widely used HFCs. The method is based on automated head‐space gas chromatography and injection of equal amount of chemical in two head‐space vials with identical air phase volumes but different volumes of the liquid phase. The liquids used were water (physiological saline), fresh human blood, and olive oil. The average λ values (n = 8) were as follows: 1,1‐difluoroethane (HFC152a) – 1.08 (blood–air), 1.11 (water–air) and 5.6 (oil–air); 1,1,1‐trifluoroethane (HFC143a) – 0.15, 0.15 and 1.90; 1,1,1,2‐tetrafluoroethane (HFC134a) – 0.36, 0.35 and 3.5; 1,1,1,2,2‐pentafluoroethane (HFC125) – 0.083, 0.074 and 1.71; and 1,1,1,3,3‐pentafluoropropane (HFC245fa) – 0.62, 0.58 and 12.1. The λ values appeared to be concentration‐independent in the investigated range (2–200 ppm). In spite of the low λ values, the method errors were modest, with coefficients of variation of 9, 11 and 10% for water, blood and oil, respectively. Copyright © 2009 John Wiley & Sons, Ltd.     

Drug‐facilitated sexual assault (DFSA) involving 4‐methylethcathinone (4‐MEC), 3,4‐Methylenedioxypyrovalerone (MDPV), and doxylamine highlighted by hair analysis

Recently, the emergence of new psychoactive substances (NPS) has led to their wide use among clubbers and men who have sex with men (MSM) for their stimulant effects. However, their use in drug‐facilitated sexual assault (DFSA) has rarely been described. Herein we report a case of a 44‐year‐old man who was assaulted after a party. Due to late reporting of the offense, only hair (black) was sampled 15 days later and a segmental analysis was achieved to look for most DFSA agents and NPS. Twenty mg of each segment (A: 0–1 cm, B: 1–3 cm, and C: 3–5 cm) were incubated in phosphate buffer pH 5.0. After alkaline liquid extraction and chromatographic separation on 1.9 μm Hypersil GOLD PFP column, compounds were detected by a TSQ Vantage mass spectrometer with electrospray ionization in positive mode with multiple reaction monitoring (MRM) acquisition. 4‐methylethcathinone (4‐MEC), methylenedioxypyrovalerone (MDPV) and doxylamine were found in proximal segment at very low concentrations (3, 5, and 9 pg/mg, respectively) which is in agreement with a single exposure in the previous month corresponding to the alleged facts. These substances were not detected in segments B and C showing a lack of repetitive exposure before the alleged event. Thus, the results do not contradict the patient's claim of being assaulted. Doxylamine has already been encountered in such cases but no publications referring to 4‐MEC or MDPV use have ever been documented. Our case reports the unusual administration of cathinones to achieve a sexual assault and stresses the interest of looking for designer drugs when dealing with DFSA cases.     

Physicochemical Properties and Pharmacological Activity of Mn(II), Fe(II), Co(II), Cu(II), AND Zn(II) Gluconates

Pharmaceutical Chemistry Journal -