1,721,050 research outputs found
Synthesis and in vitro pharmacological activity of oxypropanol analogs of labetalol
No full textAt present α- and β-adrenoceptors are classified into α1/α2 and β1/β2 (and also β3) [1] and [2] subtypes on the basis of structural and pharmacological studies. Both α- and β-adrenoceptor antagonists were proved to be effective and useful in the treatment of hypertension. β-Blockers, especially those selectively blocking heart β-adrenoceptors (β1) with little or no activity on bronchial or vascular adrenoceptors (β2), have been widely used and tested on a numbers of patients in all major multicentre intervention trials performed during past years [3], [4] and [5]. α-Adrenoceptor blocking agents have been less widely applied, although selective α1-adrenoceptor antagonists, like prazosin, have been introduced as useful antihypertensive agents. Therapeutically, the combination of α1 and β1-adrenoceptor antagonists is a logical one [6]. These observations led to the synthesis of several compounds combining both α- and β-adrenergic antagonist activities, and labetalol [1] is the first example of combined α- and β-adrenoceptor antagonistic drug [7]
Changes in rectal temperature and ECoG spectral power of sensorimotor cortex elicited in conscious rabbits by i.c.v. injectionof GABA, GABAA and GABAB agonists and antagonists
No full text1. In order to ascertain whether both GABA(A) and GABA(B), or only GABA(B) receptors, directly modulate thermoregulation in conscious rabbits, GABA(A)/GABA(B) agonist and antagonist agents were injected intracerebroventricularly in conscious rabbits while monitoring changes in rectal temperature (RT), gross motor behaviour (GMB) and electrocorticogram (ECoG) power spectra (ps) from sensorimotor cortices. 2. GABA (48 micromol), nipecotic acid (50 nmol), THIP (60 nmol), muscimol (18 nmol) and baclofen (8 nmol) induced hypothermia (-deltaRTmax values of 1.70+/-0.1, 1.4+/-0.2, 1.0+/-0.4, 1.1+/-0.2 and 1.6+/-0.3 degrees C, respectively), accompanied by inhibition of GMB and ECoG synchronization. THIP increased ps at delta frequency band (1.1-3.3 Hz), while GABA, nipecotic acid, muscimol and baclofen did the same at both delta and (4.6-6.5 Hz) frequency bands. ECoG ps changes were concomitant or even preceded hypothermia. 3. Bicuculline (1.8 nmol) induced hyperthermia (deltaRTmax 1.2+/-0.5 degrees C) and slight excitation of GMB, while CGP35348 (1.2 micromol) did not affect RT nor GMB. Both compounds did not affect ECoG ps. 4. Bicuculline potentiated muscimol-induced hypothermia, inhibition of GMB and synchronization of ECoG, while CGP35348 fully antagonized these effects. 5. In conclusion, the present results, while confirming the prevailing role of GABA(B), also outline a direct involvement of GABA(A) receptors in the central mechanisms of thermoregulation. Ascending inhibition towards discrete cortical areas controlling muscular activity and thermogenesis may result from GABA receptor activation in neurones proximal to the ventricles, thus contributing to hypothermia, although hypothermia-induced reduction of neuronal activity of these cortical areas cannot be ruled out
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
Distribution and peroxidative oxidation of 2-t-butyl-4-methoxyphenol in rat tissues after a single intraperitoneal dose
No full textThe distribution of 2-t-butyl-4-methoxyphenol (BHA) and its conversion to 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethoxydiphenyl (di-BHA) in rat tissues at different times (1-96 hr) following the intraperitoneal administration of a single dose of BHA (32 mg kg-1 body weight) were monitored by gas chromatography-mass spectrometry (GC/MS) analysis of both compounds. High BHA levels were found in the intestine and liver persisting up to 24 hours (5.5-20.7 and 1.8-3.3 micrograms g-1 wet weight, respectively). In these tissues, values of the area under the experimental concentration curve (AUC0-24) were 285 and 49 times higher, respectively, than those observed in plasma (945 ng mL-1 hr), AUC0-24 values in kidney, spleen, erythrocytes, and brain were 2-7 times higher, whereas values below those found in plasma were observed in lung and muscle. The metabolite di-BHA could be detected in the intestine, kidney, and spleen, amounting to 5-8% of BHA. These findings indicate that rat intestine is capable of transforming in vivo BHA into di-BHA even when the former compound is administered intraperitoneally and that this capacity is shared by the kidney and spleen
Neuroprotection afforded by GABA against oxygen-glucose deprivation-induced injury in rat cortical brain slices: an hormetic dose-response effect
No full textThe aim of the present investigation was to assess neuroprotection exerted by GABA (100
nM-100 mM) 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 GABA exerted neuroprotective
effects according to a U-shaped, hormetic-like, concentration-response curve, with an efficacy window
of 10-100 μM concentration. In order to verify whether GABA-neuroprotective effects were GABAAor
GABAB-mediated, Muscimol (GABAA agonist) and Baclofen (GABAB agonist) were tested. Results
demonstrated that only Muscimol exerted neuroprotection according to a U-shaped, hormetic-like,
concentration-response curve, while baclofen was ineffective. In conclusion, the hormetic response of
GABA or GABAA agonists should be taken into consideration when designing experiments aimed at
assessing neuroprotection by these agents against ischemia/reoxygenation injury
Thin layer chromatography in the quantitative analysis of pharmaceuticals. Comparison of layers in the analysis of complex mixtures of phenothiazine derivatives
No full textProtection by taurine of rat brain cortical slices against oxygen glucose deprivation- and reoxygenation-induced damage
No full textTaurine neuroinhibitory features have suggested its potential for neuroprotection. The aim of the present study was to assess whether it prevents or counteracts brain ischemia and reperfusion-induced cell injury. Rat brain cortical slices were subjected to oxygen/glucose deprivation and reperfusion. Tissue damage was assessed by measuring the release of glutamate and lactate dehydrogenase (LDH) during reperfusion and by determining final tissue water gain, taken as an index of cell swelling. When added during the reperfusion period taurine did not significantly affect oxygen/glucose deprivation-induced LDH and glutamate release, while it antagonised tissue water gain in a concentration-dependent manner (IC(50)=46.5 microM). The latter effect was antagonised by 50% when a taurine transport inhibitor, 2-(guanidino)ethanesulphonic acid (GES), or a GABA(A) receptor antagonist, bicuculline, was added together with taurine, while it was completely abolished when both GES and bicuculline or the volume-sensitive outwardly rectifying (VSOR) Cl(-) channel blocker, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), was used. On the contrary, when present throughout the entire experiment, taurine significantly reduced oxygen/glucose deprivation-induced LDH and glutamate release with a maximal effect (45% reduction) between 5 and 20 mM. Taurine antagonised also tissue water gain according to a "U-shaped" concentration-response curve, which was significant within the range of 0.01-1.0 mM concentration. This effect was partially counteracted by GES as well as by bicuculline and fully reverted by NPPB. In conclusion, since brain edema is a major contributing factor to morbidity and mortality in stroke, the present findings give the rational basis for assessing taurine efficacy in reducing brain edema in vivo
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
Non-steroidal antiinflammatory agents. Synthesis and enzyme inhibition of 2-[4-(heteroarylmethyl)phenil] propanoic acids and analogues
No full textSome 2-[4-(heteroarylmethyl)phenyl]propanoic acids and phenylacetic and benzoic analogues has been synthesized. All above acids were tested for their inhibitory activity on lipoxygenase and cyclooxygenase, in comparison with NDGA and tolmetin. 2-[4-(Thien-2-ylmethyl)phenyl]propanoic acid 2, strictly related with suprofen, was found the most interesting compound, giving rise to a 79% inhibition of the cyclooxygenase activity at 10(-4) M concentration
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