Interaction of guanidinium compounds and K+ channel modulators with imidazoline binding sites in rabbit kidney.

Several guanidinium compounds were tested for their ability to inhibit the binding of [3H]idazoxan to the I2 subtype of the imidazoline site on rabbit kidney basolateral membranes. Phenformin, a biguanide, was the most potent with an IC50 of 50 +/- 3 microM. Various K+ channel modulators were also evaluated for inhibition of [3H]idazoxan binding.

Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist.

We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol - 5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AII) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT1 receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.

Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists.

2,5-Dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4' - yl]methyl]-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action. To explore the lipophilic pocket in the AII receptor interacting with the substituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinity and antagonism of AII-contracted rabbit aortic rings. It has been found that the pocket is very spacious and can accommodate different sizes of lipophilic groups and various functionalities.

Nonpeptide angiotensin II antagonists: N-phenyl-1H-pyrrole derivatives are angiotensin II receptor antagonists.

A series of 5-[1-[4-[(4,5-disubstituted-1H-imidazol-1-yl)methyl]- substituted]-1H-pyrrol-2-yl]-1H-tetrazoles and 5-[1-[4-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-substituted]- 1H-pyrrol-2-yl]-1H-tetrazoles were investigated as novel AT1-selective angiotensin II receptor antagonists. Computer-assisted modeling techniques were used to evaluate structural parameters in comparison to the related biphenyl system. New synthetic procedures have been developed to prepare the novel compounds.

In vitro pharmacology of a nonpeptidic angiotensin II receptor antagonist, SC-51316.

The properties of a novel nonpeptidic angiotensin II (AII) receptor antagonist, 2,5-dibutyl-2,4-dihydro-4-([2-(1H-tetrazol-5-yl)(1,1'-biphenyl) -4'-yl]methyl)-3H-1,2,4-triazol-3-one (SC-51316), are described. SC-51316 inhibited [125I]AII binding selectively to the AT1 receptor with IC50 values of 3.6 and 5.

Reversal of enhanced muscle glucose transport after exercise: roles of insulin and glucose.

Exercise stimulates insulin-independent glucose transport in skeletal muscle and also increases the sensitivity of the glucose transport process in muscle to insulin. A previous study [D. A.

Characterization of a [3H]glycine recognition site as a modulatory site of the N-methyl-D-aspartate receptor complex.

A [3H]glycine recognition site in rat brain synaptic plasma membranes (SPM) has been identified, having characteristics expected of a modulatory component of the N-methyl-D-aspartate receptor complex. Incubation of SPM with [3H]glycine for 10 min at 2 degrees C results in saturable, reversible binding with a KD of 0.234 microM and a Bmax of 9.

NAD+-induced inhibition of phosphate transport in canine renal brush-border membranes. Mediation through a process other than or in addition to NAD+ hydrolysis.

We previously demonstrated inhibition of Na+-dependent 32Pi transport in canine renal brush-border membranes in association with NAD+-induced ADP ribosylation of membrane protein(s) and postulated that NAD+ inhibits Pi transport across the brush-border membrane via ADP ribosylation. Recently it was shown that incubation of rat brush-border membrane with NAD+ resulted in release of Pi which was prevented by EDTA. It was proposed that NAD+-mediated inhibition of 32Pi transport might occur through this mechanism.

Effects of ATP on calcium binding to synaptic plasma membrane.

The release of labeled norepinephrine from preloaded synaptosomes requires the presence of potassium and calcium. ATP-dependent binding of calcium to synaptic plasma membranes (SPM) may provide a means of maintaining the cation in a readily available pool for the triggering of transmitter release. A high Ca-binding capacity was demonstrated in SPM.