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EFFECTS OF CLOZAPINE ON RAT STRIATAL MUSCARINIC RECEPTORS COUPLED TO INHIBITION OF ADENYLYL CYCLASE ACTIVITY AND ON THE HUMAN CLONED M4 RECEPTOR
No full text1. Clozapine has recently been claimed to behave as a selective and full agonist at the cloned m4 muscarinic receptor artificially expressed in Chinese hamster ovary (CHO) cells. In the present study we have investigated whether clozapine could activate the rat striatal muscarinic receptors coupled to the inhibition of adenylyl cyclase activity, considered as pharmacologically equivalent to the m4 gene product. In addition, we have examined the effect of the drug on various functional responses following the activation of the cloned m4 receptor expressed in CHO cells. 2. In rat striatum, clozapine (1 nM-10 microM) caused a slight inhibition of forskolin-stimulated adenylyl cyclase activity, which was not counteracted by 10 microM atropine. On the other hand, clozapine antagonized the inhibitory effect of acetylcholine with a pA2 value of 7.51. Moreover, clozapine (1 microM) failed to inhibit dopamine D1 receptor stimulation of adenylyl cyclase activity, but counteracted the inhibitory effect of carbachol (CCh). Clozapine displaced [3H]-N-methylscopolamine ([3H]-NMS) bound to striatal M4 receptors with a monophasic inhibitory curve and a pKi value of 7.69. The clozapine inhibition was not affected by the addition of guanosine-5'-O-(thio)triphosphate (GTPgammaS). 3. In intact CHO cells, clozapine inhibited forskolin-stimulated cyclic AMP accumulation with an EC50 of 31 nM. This effect was antagonized by atropine. CCh produced a biphasic effect on cyclic AMP levels, inhibiting at concentrations up to 1 microM (EC50=50 nM) and stimulating at higher concentrations (EC50 = 7 microM). Clozapine (0.3-5 microM) antagonized the CCh stimulation of cyclic AMP with a pKi value of 7.47. Similar results were obtained when the adenylyl cyclase activity was assayed in CHO cell membranes. 4. In CHO cells pretreated with the receptor alkylating agent 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (10 microM), the maximal inhibitory effect of clozapine on cyclic AMP formation was markedly reduced, whereas the CCh inhibitory curve was shifted to the right with no change in the maximum. 5. As in rat striatum, in CHO cell membranes the displacement of [3H]-NMS binding by clozapine yielded a monophasic curve which was not affected by GTPgammaS. 6. Clozapine (10 nM-10 microM) had a small stimulant effect (approximately 20%) on the binding of [35S]-GTPgammaS to CHO cell membranes, whereas CCh caused a 250% increase of radioligand binding. Moreover, clozapine (50 nM-5 microM) antagonized the CCh-stimulated [35S]-GTPgammaS binding with a pA2 value of 7.48. 7. These results show that at the striatal M4 receptors clozapine is a potent and competitive antagonist, whereas at the cloned m4 receptor it elicits both agonist and antagonist effects. Thus, clozapine behaves as a partial agonist, rather than as a full agonist, at the m4 receptor subtype, with intrinsic activity changing as a function of the coupling efficiency of the receptor to effector molecules
“Elevata produzione di proteine ricombinanti da un ceppo di Kluyveromyces lactis coltivato su reflui dell’industria casearia”
No full textValutazione dell'attività antivirale del lisozima e suoi derivati mediante l'uso di un apparato coulter counter
No full text[Phe(1)Phi(CH2-NH)Gly(2)]nociceptin-(1-13)-NH2 acts as a partial agonist at ORL1 receptor endogenously expressed in mouse N1E-115 neuroblastoma cells
No full textTHE nociceptin derivative [Phe(1)Phi(CH2-NH)Gly(2)]-nociceptin-(1-13)-NH2 (Phe Phi noc) has been reported to act either as a simple antagonist or as a full agonist at the opioid receptor-like (ORL1) receptor. In the present study, we identified the expression of the ORL1 receptor in murine N1E-115 neuroblastoma cells and used this neuronal system to investigate the pharmacological activity of Phe Phi noc. Like nociceptin, Phe Phi noc stimulated the binding of [S-35]GTP gamma S (EC50 = 120 nM) and inhibited forskolin-stimulated [H-3]cAMP formation (EC50=3.3 nM). However, Phe Phi noc elicited maximal effects lower than those induced by nociceptin, and when combined with nociceptin potently antagonized the responses to the natural agonist (K-i = 0.9 nM). These data indicate that Phe Phi noc acts as a partial agonist at the ORL1 receptor endogenously expressed in N1E-115 cells. NeuroReport 10:1127-1131 (C) 1999 Lippincott Williams & Wilkins
A rapid method for screening large numbers of environmental microorganisms for antiviral activity
No full textMixed agonist-antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells
No full textWe recently reported that clozapine behaves as a partial agonist at the cloned human m4 muscarinic receptor subtype. In the present study, we investigated whether the drug could elicit similar effects at the cloned human m1, m2, and m3 muscarinic receptor subtypes expressed in the Chinese hamster ovary (CHO) cells. Clozapine elicited a concentration-dependent stimulation of [3H]inositol phosphates accumulation in CHO cells expressing either the m1 or the m3 receptor subtype. Moreover, clozapine inhibited forskolin-stimulated cyclic AMP accumulation and enhanced [35S] GTP gamma S binding to membrane G proteins in CHO cells expressing the m2 receptor. These agonist effects of clozapine were antagonized by atropine. The intrinsic activity of clozapine was lower than that of the full cholinergic agonist carbachol, and, when the compounds were combined, clozapine potently reduced the receptor responses to carbachol. These data indicate that clozapine behaves as a partial agonist at different muscarinic receptor subtypes and may provide new hints for understanding the receptor mechanisms underlying the antipsychotic efficacy of the drug
High-level production of heterologous protein by engineered yeasts grown in cottage cheese whey
No full textCottage cheese whey is a cheese industry by-product still rich in proteins and lactose. Its recycling is seldom cost-effective. In this work we show that the lactose-utilizing yeast Kluyveromyces lactis, engineered for production of recombinant human lysozyme, can be grown in cottage cheese whey, resulting in high-level production of the heterologous protein (125 mu g/ml)
Karalicin, a new biologically active compound from Pseudomonas fluorescens/putida. I: production, physico-chemical properties and structure elucidation.
No full textAntifungal, antibacterial, antiviral and cytotoxic activity of novel thio- and seleno-azoles
No full textA series of pentaatomic heterocyclic compounds containing sulphur or selenium in position 2, were tested for cytotoxicity, antiviral and antimicrobial activities. Generally, selenium-containing compounds were more toxic than the corresponding sulphur-containing ones (30-75 times more toxic) and, furthermore, the biological activity against some microorganisms was also enhanced. In particular, some selenium-containing derivatives exerted an inhibitory activity on plant pathogenic fungi at doses markedly lower than the toxic ones, showing an interesting selectivity of action. In this case the tested compounds appeared more active than ketoconazole, the control used, with an almost comparable degree of cytotoxicity
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