186,326 research outputs found
SEARCH FOR SELECTIVE ANTAGONISTS AT α1-ADRENORECEPTOR SUBTYPES: WB-4101 RELATED COMPOUNDS
No full textThe development of subtype selective α1 ligands is intensively pursued in order to obtain more effective and safer agents for the treatment of cardiovascular pathologies such as hypertension and arrhythmia, but also and particularly of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).
One of the oldest and most potent α1 antagonists is represented by WB-4101, a 2-aminomethyl-1,4-benzodioxane derivative which is slightly selective for α1A and, to a minor extent, for α1D-ARs with respect to α1B-AR and 5-HT1A serotoninergic receptor. Many structural modifications of WB-4101 have been done to improve both affinity and selectivity.1-4 Some evidences, resulting from mutagenesis and docking studies, suggest that the benzodioxane moiety and the 2,6-dimethoxyphenoxy residue of WB-4101 are, respectively, involved in conferring α1a selectivity and high α1 affinity. Consistently with these findings, our recent researches have demonstrated that removal of one or both ortho-methoxy substituents adversely affects the affinity for the three α1-AR subtypes, but not that for the 5-HT1A receptor.3
On the basis of these indications, we synthesized a number of S and R analogues of WB-4101, characterized by different substitutions at the benzodioxane and/or phenoxy fragment, in order to modulate and, hopefully, to improve the activity and selectivity profile of the parent compound. In particular, we considered derivatives with benzodioxane 8-substituted with F,4 Cl, OH or OMe 4 or fused with a cyclohexane to give a tetrahydronaphthodioxane polycycle.2 On the other hand, 2,6-dimethoxyphenyl residue was replaced by ortho methoxy substituted 1-naphthyl 2 or biphenyl systems. Finally, hybrid structures were designed combining some of the above modifications. After binding assays, which demonstrated the better α1a, α1b, α1d and 5-HT1A affinity of the S enantiomers, these latter were tested in functional assays on isolated tissues, finding that almost all were able to discriminate among the α1-AR subtypes.
1. Bolognesi M.L., Budriesi R., Cavalli A., Chiarini A., Gotti R., Leonardi A., Minarini A., Poggesi E., Recanatini M., Rosini M., Tumiatti V., Melchiorre C. J.Med.Chem. 1999, 42, 4214-4224.
2. Bolchi C., Catalano P., Fumagalli L., Gobbi M., Pallavicini M., Pedretti A., Villa L., Vistoli G., Valoti E. Bioorg.Med.Chem. 2004, 12, 4937-51.
3. Fumagalli L., Bolchi C., Colleoni S., Gobbi M., Moroni B., Pallavicini M., Pedretti A., Villa L., Vistoli G., Valoti E. Bioorg.Med.Chem. 2005, 13, 2547-2559.
4. Valoti E., Pallavicini M., Villa L., Pezzetta D. J.Org.Chem. 2001, 66, 1018-1025
Interactions between substituted tryptamine analogues, MAO inhibitors and cytochrome P-450
No full textThe effects of some MAO inhibitors, N-acetylenic analogues of tryptamine, on rat liver microsomal cytochrome P-450 (cyt P-450) have been investigated. All the compounds tested interacted with cyt P-450 with Ks values ranging between 14 and 358 microM (clorgyline Ks = 10.5 microM). Compounds with a tertiary amine and those possessing a secondary amine group in the acetylenic side chain exhibited type I and type II difference spectra, respectively. Aniline hydroxylase activity was inhibited irreversibly and in a time-dependent fashion by all compounds tested with IC50 ranging between 7 x 10(-5) and 7 x 10(-3) M (clorgyline 10(-4) M)
Sviluppo e validazione di un metodo HPLC-FLD per la determinazione di 4’-O-metilpiridossina nei semi di Ginkgo biloba L.
No full textI semi di Ginkgo biloba sono ampiamente utilizzati nella cucina tradizionale cinese sia per il loro valore nutrizionale sia per le caratteristiche organolettiche. È però noto che i semi di questa pianta possono essere responsabili di eventi avversi a causa della possibile presenza della 4’-O-metilpiridossina, conosciuta anche come ginkgotossina. Questa molecola ad azione neurotossica è strutturalmente simile alla vitamina B6, di cui altera, a elevate concentrazioni, il metabolismo e le funzioni fisiologiche (1). I soggetti maggiormente sensibili agli eventi avversi sono i bambini, a causa del ridotto peso corporeo e della loro limitata capacità metabolica.
Il presente lavoro ha origine da un caso di avvelenamento occorso in un bambino di 23 mesi che, in seguito a ingestione di un numero elevato ma imprecisato di semi di Ginkgo biloba, ha manifestato crisi convulsive tonico-cloniche in assenza di febbre (2).
Al fine di garantire la sicurezza d’uso nel consumo dei semi e, considerando come la cucina asiatica si stia rapidamente diffondendo nei Paesi occidentali, è evidente la necessità di condurre approfonditi studi per la caratterizzazione e la quantificazione dell’MPN.
A tale scopo, una nuova metodica cromatografica HPLC (accoppiata a fluorimetro) è stata messa a punto e convalidata seguendo le linee guida del protocollo FDA relativo ai metodi bioanalitici (2013).
I parametri tecnici di validazione valutati sono: 1) idoneità del sistema, 2) precisione, 3) linearità, 4) recupero. Tali parametri soddisfano i criteri di accettabilità imposti dalle linee guida: il coefficiente di correlazione R2 > 0.98 indica una soddisfacente linearità del metodo e la metodica messa a punto risulta sufficientemente sensibile, come dimostrato dai valori di LOD e LOQ pari a 0.14 ng/mL e 0.47 ng/mL, rispettivamente. Tali valori corrispondono a un quantitativo di MPN nel campione pari a 2.8 ng/g e 9.4 ng/g, rispettivamente.
La metodica messa a punto è stata infine applicata ad alcuni campioni di origine giapponese. Il contenuto di ginkgo tossina rilevato nei campioni è di 325.53±114.12 μg/g. Pur evidenziando una notevole variabilità nel contenuto di ginkgotossina, essa è risultata in accordo con i valori presenti in letteratura (compresi tra 170 e 400 μg/g).
La metodica cromatografica è risultata quindi idonea, efficace, riproducibile e adatta all’analisi dei semi di ginkgo per la conferma della presenza e quantificazione della 4’-O-metilpiridossina.
Il metodo verrà applicato a un numero più elevato di campioni allo scopo di confermare i dati ottenuti e per valutare, in parallelo, l’eventuale influenza dell’origine geografica sul contenuto di MPN.
Riferimenti bibliografici
1. Arenz, A., Klein, M., Fiehe, K., Groβ, J., Drewke, C., Hemscheidt, T, Leistner, E. 1996. Occurrence of neurotoxic 4'-methylpyridoxine in Ginkgo biloba leaves, gingko medications and Japanese ginkgo food. Planta Med 62, 548-551.
2. Di Lorenzo, C., Ceschi, A., Colombo, F., Frigerio, G., Bianchetti, M.G., Lude, S., Von Dechend, M., Valoti, E., Restani, P., 2015. Identification and quantification of biomarkers to confirm the poisoning by Ginkgo biloba seeds in a 2-years-old boy; Toxicol. Res., 4, 922-930
The interaction of antioxidants and structurally related compounds with mitochondrial oxidative phosphorylation
No full textThe antioxidants, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), interact with mitochondrial oxidative phosphorylation in two ways. They uncouple phosphorylation from oxidation by making the mitochondrial inner membrane more permeable to protons. They also inhibit respiration by a direct interaction with the electron transport chain. Here we separated out these two properties of BHA and BHT by determining their effects on respiration in coupled and uncoupled mitochondria. Similar experiments were carried out with compounds structurally related to BHA and BHT. Most of these compounds had uncoupling and inhibitory properties essentially similar to BHA and BHT. In contrast, the dimer of BHA had no inhibitory effects on uncoupled respiration and little uncoupling activity. The implications of these results for the interactions of BHA and BHT with mitochondrial oxidative phosphorylation and the design of antioxidants are discussed
Oxidative ring-coupling of tyrosine and its derivatives by purified rat intestinal peroxidase
No full textIntestinal peroxidase was shown to catalyse the oxidative ring-coupling of tyrosine, alpha-methyltyrosine, tyramine and morphine whereas amphetamine was not oxidized to any detectable extent. The oxidative ring-coupling reaction can be monitored by changes in absorbance spectra and the dimers formed in this way with morphine and alpha-methyltyrosine were identified by mass spectrometry. Intestinal peroxidase also catalysed the peroxidatic oxidation of L-DOPA and alpha-methyl-L-DOPA, but in this case the reaction would be expected to be more complicated and to yield a variety of possible products. The kinetic parameters for the oxidation of each of these substrates were determined. Since the products of the oxidative ring-coupling reactions may have different pharmacological properties to those of the parent compounds, these studies suggest that, in the presence of an adequate supply of metabolically produced hydrogen peroxide, the action of intestinal peroxidase may affect the behaviour and pharmacokinetics of these compounds after oral administration
Diastereomeric 2-aminomethyl-1,4-benzodioxane mandelates : phase diagrams and resolution
No full textThe diastereomeric salts of (R)- and (S)-2-aminomethyl-1,4-benzodioxane with unichiral mandelic acid form a simple eutectic, whose binary phase melting point diagram shows the unique eutectic at 0.35 M ratio of the less soluble diastereomer. Such an eutectic composition, near to 0.5, is consistent with the modest efficiency previously reported for their separation via crystallization from ethanol/ethyl acetate. However, the ternary solubility phase diagram, obtained from solubility measurements in methanol, shifts the eutectic to a lower molar ratio (0.10) of the less soluble diastereomer, thus indicating an optimal resolvability of the diastereomeric mandelates. This was confirmed by the highly efficient resolution of racemic 2-aminomethyl-1,4-benzodioxane with (R)-mandelic acid via a single crystallization from methanol. The ready availability of both the racemic substrate and the resolving acid makes this simple and efficient resolution procedure very attractive to obtain the enantiomers of 2-aminomethyl-1,4-benzodioxane, which are important synthetic intermediates
From 2-aminomethyl-1,4-benzodioxane enantiomers to unichiral 2-cyano- and 2-carbonyl-substituted benzodioxanes via dichloroamine
No full text2-Substituted 1,4-benzodioxanes, such as 2-cyano-, 2-methoxycarbonyl-, 2-aminocarbonyl-, and 2-formyl-1,4-benzodioxane, are key synthons that for the most part are never described as enantiomers or are inadequately characterized for enantiomeric purity. They were prepared by quantitative N,N-dichlorination of (R)- and (S)-2-aminomethyl-1,4-benzodioxane and successive functional group conversions in high yields without any racemization of the stereogenic benzodioxane C(2)
Inhibition of iron-dependent decomposition of H2O2 as a method for assessing the free-radical-scavenging activity of novel antioxidant in a hydrophilic enviroment
No full textBiotechnologica sulphated chondroitin sulphate at position 4 or 6 on the same polysaccharide chain, and process for the preparation thereof
No full textThe present invention disclosed a process for the production of chondroitin sulphated with an average molecular weigh (Mw) of 10-30 KDa by chemical sulphation starting from an unsulphated backbone, obtained in turan by acidc hydrolisis of capsular polysaccarides K4 made directly from E. coli strai O5:K4:H14, ordirectly produced from a genetically modified strain of E. coli. Sulphatetion of N-acetil-D-galactosamine residue at position 4 or 6 takes place simultaneously in the same plisaccharide chain, simulating the sulphation pattern observed in natural chondroitin sulphate, unlike the sukphation obtained with the synthesis methods described to date
Neuroprotection afforded by diazepam against oxygen/glucose deprivation-induced injury in rat cortical brain slices
No full textThe aim of the present investigation was to assess neuroprotection exerted by diazepam (0.1-25 microM) in rat cortical brain slices subjected to oxygen-glucose deprivation and reoxygenation. Neuronal injury and neuroprotection were assessed by measuring the release of glutamate and lactate dehydrogenase and tissue water content. Results demonstrate that diazepam exerted neuroprotective effects according to a "U-shaped", hormetic-like, concentration-response curve, with an efficacy window of 0.5-5 microM concentration. Flumazenil (20 microM) fully antagonised neuroprotection afforded by 5 microM diazepam. In conclusion, the hormetic response of diazepam should be taken into consideration when designing experiments aimed at assessing diazepam neuroprotection against ischemia/reoxygenation injury
- …
