Biomedical subjects
Publications and source records attributed to N L Wiech.
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[3H]Nitrendipine [( 3H]NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,330A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing [3H]NTD binding in membranes prepared from the cerebral cortex and the heart, with EC50 values of 6.1 X 10(-8) and 3.4 X 10(-8) M, respectively, at 37 degrees C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance [3H]NTD binding at 37 degrees C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37 degrees C greater than 25 degrees C greater than 0 degrees C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of [3H]NTD binding.
Alpha-[4-(1,1-Dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) inhibition of the in vitro binding of [3H]mepyramine to histamine H1-receptors prepared from guinea pig brain and ileum was characterized under several experimental conditions. After an intraperitoneal injection of 5 mg/kg of either terfenadine or chlorpheniramine, brain and ileum were obtained to determine in vitro the binding of [3H]mepyramine to histamine H1-receptors. While the binding of ligand to receptors from the ileum of both terfenadine and chlorpheniramine treated animals was almost completely inhibited, the ligand binding to receptors from brains of chlorpheniramine treated but not terfenadine treated animals was affected. When terfenadine was added to receptor homogenates from guinea pig brain and ileum, it antagonized the binding of [3H]mepyramine to receptors from both tissues. The potency of terfenadine antagonism of ligand binding was similar to both ileal (IC50, 200 nmol/l) and brain (IC50, 300 nmol/l) receptors. The kinetics of in vitro antagonism by terfenadine of [3H]mepyramine binding to receptors is unique in that antagonism of ligand binding by terfenadine was enhanced by a longer incubation of the receptors with this drug and H1-receptor blockade by terfenadine could not be reversed by extensive washing of these receptors at 25 degrees C. These results show that terfenadine treatment does not result in sufficient levels in the brain to inhibit central histamine receptors at a dose which overwhelmingly inhibits histamine receptors in peripheral tissue. It is proposed that terfenadine slowly associates with the H1-receptor and forms a stable complex from which it dissociates quite slowly.
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A series of alpha-cycloalkylphenylmethyl lactamimides and a series of furan- and thiophenealkyl lactamimides were prepared for biological evaluation as an extension of earlier finding of hypoglycemic activity in lactamimides. Compounds 7, 20, 23, 25, 29, and 32 produced pronounced hypoglycemia after oral administration to fasted, glucose-primed rats.
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Three-month old germfree and conventional male rats were maintained on a complete steam-sterilized, semisynthetic diet. After intravenous injection of cholesterol-26-(14)C the animals were housed in a plastic metabolism chamber for 72 hr. Expired CO(2) was collected throughout the period. The conventional rats released 50% more (14)C as (14)CO(2) than the germfree animals. The total amount of the label recovered as (14)CO(2) during the 72 hr period amounted to 30% and 19% respectively, of the original dose. In both conventional and germfree rats the release of (14)CO(2) accounted for approximately 75% of the (14)C recovered in forms other than the original cholesterol-26-(14)C; 15-20% was found incorporated in water-soluble and fat-soluble fractions other than 3Beta-OH sterol of liver and carcass while the remainder was excreted with feces and urine. After the 72 hr period the specific activities of the cholesterol in plasma and liver were lower in conventional than in germfree animals. The data express the accelerating effect of the intestinal microflora on systemic cholesterol catabolism. They demonstrate that the release of (14)CO(2) from cholesterol-26-(14)C in the intact rat is a suitable and convenient indicator of the oxidative catabolism of cholesterol.