PubMed · 4405676
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S Sterkowicz. 1973-01-22. [Intravenous practolol test].. https://pubmed.ncbi.nlm.nih.gov/4405676/
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A series of modifications were made to the C-3 substituent of the 1,5-benzodiazepine CCK-A agonist 1. Replacement of the inner urea NH and addition of a methyl group to generate a C-3 quaternary carbon resulted in acetamide 6, which showed CCK-A receptor binding selectivity and sub-micromolar agonist activity in vitro. Benzodiazepine 6 was active in an in vivo mouse gallbladder emptying assay and represents a novel orally active, binding selective CCK-A agonist.
BACKGROUND: Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts. METHODS AND RESULTS: Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate; with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and glucose oxidation were measured with the use of [5-3H/U-14C]-glucose and FA oxidation with the use of [1-14C]- or [9,10-3H]-palmitate. In working hearts, 10 micromol/L ranolazine significantly increased glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production was low (low Ca, high FA, with insulin), high (high Ca, low Fa, with pacing), or intermediate. In some cases, reductions in FA oxidation were seen. No substantial changes in glycolysis were noted with/without ranolazine; rates were approximately 10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting. Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses. In normoxic Langendorff hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared with working hearts, but 10 micromol/L ranolazine similarly increased glucose oxidation; ranolazine also significantly increased it during flow reduction to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or hemodynamic parameters or O2 use. In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis. CONCLUSIONS: Beneficial effects of ranolazine in cardiac ischemia/reperfusion may be due, at least in part, to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing improved ATP/O2 and reduction in the buildup of H+, lactate, and harmful fatty acyl intermediates.
Kinetics analysis of the growth of Fusarium sporotrichioides T-424 at 15 degrees C and 25 degrees C in liquid culture for 35 days revealed that production of deacetylated trichothecenes was associated with an increased activity in fungal esterases. High temperature (25 degrees C) favored enzyme production and enhanced esterase activity. Electrophoresis of crude extracts from the mycelia of F. sporotrichioides T-424 with carboxylesterase staining revealed that several esterases were produced by the fungus. Four carboxylesterase isoenzymes (I-IV) were separated on a DEAE-Sephadex anion exchange column. Type (III) esterase, having activities with the substrate 4-nitrophenylacetate and acetanilide, as well as hydrolytic activity for T-2 toxin and acetyl-T-2 toxin, was partially purified with ammonium sulfate precipitation, immunoaffinity column chromatography, and DEAE-Sephadex A-50 chromatography. The esterase (III) had a molecular weight around 68 kDa in SDS-PAGE. For the deacylation of T-2 toxin and acetyl-T-2 toxin, type (III) esterase had a high specificity for the acetyl group at the C-3 and C-4 positions. The Km values for acetyl-T-2 and T-2 toxin were found to be 41.35 microM and 0.38 microM, respectively. The Km value for the acetyl group at C-3 is 110 times greater than for that at C-4.