Limit on the Fierz Interference Term b from a Measurement of the Beta Asymmetry in Neutron Decay.

In the standard model of particle physics, the weak interaction is described by vector and axial-vector couplings only. Nonzero scalar or tensor interactions would imply an additional contribution to the differential decay rate of the neutron, the Fierz interference term. We derive a limit on this hypothetical term from a measurement using spin-polarized neutrons.

Measurement of the Weak Axial-Vector Coupling Constant in the Decay of Free Neutrons Using a Pulsed Cold Neutron Beam.

We present a precision measurement of the axial-vector coupling constant g_{A} in the decay of polarized free neutrons. For the first time, a pulsed cold neutron beam was used for this purpose. By this method, leading sources of systematic uncertainty are suppressed.

Discovery of non-covalent dipeptidyl peptidase IV inhibitors which induce a conformational change in the active site.

A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding.

Dipeptidyl peptidase-IV inhibitors can restore glucose homeostasis in type 2 diabetics via incretin enhancement.

Incretin levels approach normal physiological values following treatment with dipeptidyl peptidase (DPP)-IV inhibitors. This is in contrast to incretin levels resulting from the exogenous administration of glucagon-like peptide (GLP)-1 and its analogs, which can reach super-physiological values. This review describes the role of DPP-IV inhibitors as incretin enhancers in the regulation of glucose homeostasis in type 2 diabetic patients.

Structure activity studies of the serine-AIB dipeptide domain in 2,3-dihydroisothiazole based growth hormone secretagogues.

A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl-D-Ser-aminoisobutyric acid dipeptide fragment. Introduction of substituents in the peptide backbone and in the phenyl ring has been investigated, as well as replacements for the benzyl group and for the AIB residue.

Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2 diabetes.

Inhibitors of the regulatory protease dipeptidyl peptidase-IV (DPP-IV) are currently under development in preclinical and clinical studies (several pharmaceutical companies, now in Phase III) as potential drugs for the treatment of type 2 diabetes. Their development is based on the observation that DPP-IV rapidly inactivates the incretin hormone glucagon-like peptide-1 (GLP-1), which is released postprandially from the gut and increases insulin secretion. DPP-IV inhibitors stabilise endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner; therefore, they do not demonstrate any hypoglycaemic effects.

A buffer temperature controlled perifusion system to study temperature dependence and kinetics of insulin secretion in MIN6 pseudoislets.

Introduction: The perifusion of pancreatic islets is a well-known method to investigate the kinetics of insulin secretion. Nevertheless, little interest has been attributed to a precise temperature control in perifusion systems. Insulin secretion from MIN6 cells, cultured as monolayers, differs substantially from pancreatic islets, at least partly due to missing beta-to-beta cell contacts.

Restoration of first-phase insulin secretion by the imidazoline compound LY374284 in pancreatic islets of diabetic db/db mice.

The effect of the imidazoline compound LY374284 has been studied in pancreatic islets of db/db mice, a progressive model of diabetes. In perifusion experiments, pancreatic islets of db/db mice showed a progressive deterioration of glucose-induced insulin release with increasing age, whereby the first phase of insulin secretion was almost completely abolished and the second phase was substantially decreased by 15 weeks of age. LY374284 restored the first phase of glucose-induced insulin secretion in islets of 16-week-old db/db mice to 70% of that observed in islets isolated from age-matched nondiabetic db/1 mice.

Inhibition of recombinant K(ATP) channels by the antidiabetic agents midaglizole, LY397364 and LY389382.

Most imidazolines inhibit ATP-sensitive K(+) (K(ATP)) channels. Since these drugs are potentially clinically relevant insulin secretagogues, it is important to know whether extrapancreatic K(ATP) channels are targeted. We examined the effects of three imidazoline-derived antidiabetic drugs on the cloned K(ATP) channel, expressed in Xenopus laevis oocytes, and their specificity for interaction with the pore-forming Kir6.

Pertussis toxin converts hyperpolarizations caused by alpha(2)-adrenoceptor agonists containing an imidazoline moiety into depolarizations in MIN 6 cells.

Several alpha(2)-adrenoceptor agonists containing an imidazoline moiety inhibit insulin secretion when applied to beta cells. In the present study we investigated such imidazolines in regard to membrane potential effects in MIN 6 cells. We confirmed the inhibition of insulin release as reported in previous studies and showed an additional hyperpolarizing activity of the imidazolines using bisoxonol for membrane potential measurements.

Insulinotropic activity of the imidazoline derivative RX871024 in the diabetic GK rat.

The insulinotropic activity of the imidazoline derivative RX871024 was compared in pancreatic islets from nondiabetic Wistar rats and spontaneously diabetic Goto-Kakizaki (GK) rats. RX871024 significantly stimulated insulin secretion in islets from both animal groups. The insulinotropic activity of RX871024 was higher than that of the sulfonylurea glibenclamide.

Glucose-induced insulin secretion is potentiated by a new imidazoline compound.

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration. This can lead to hypoglycaemia in type 2 diabetic patients. Over the last years a number of imidazoline derivatives have been identified that stimulate insulin secretion in a more glucose-dependent way.

The novel imidazoline compound BL11282 potentiates glucose-induced insulin secretion in pancreatic beta-cells in the absence of modulation of K(ATP) channel activity.

The insulinotropic activity of the novel imidazoline compound BL11282 was investigated. Intravenous administration of BL11282 (0.3 mg x kg(-1) x min(-1)) to anesthetized rats did not change blood glucose and insulin levels under basal conditions, but produced a higher increase in blood insulin levels and a faster glucose removal from the blood after glucose infusion.

Imidazoline RX871024 raises diacylglycerol levels in rat pancreatic islets.

Imidazoline compound RX871024 and carbamylcholine (CCh) stimulate insulin secretion in isolated rat pancreatic islets. Combination of CCh and RX871024 induces a synergetic effect on insulin secretion. RX871024 and CCh produce twofold increases in diacylglycerol (DAG) concentration.

Fused bicyclic Gly-Asp beta-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere.

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds.

Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa.

Different modes of action of the imidazoline compound RX871024 in pancreatic beta-cells. Blocking of K+ channels, mobilization of Ca2+ from endoplasmic reticulum, and interaction with exocytotic machinery.

The imidazoline compound RX871024 glucose-dependently potentiates the release of insulin in pancreatic islets and beta-cell lines. This activity of the compound is not related to its action by stimulating alpha 2-adrenoceptors and I1- and I2-imidazoline receptors. There are at least three modes of action of RX871024 in beta-cells: (1) RX871024 blocks the ATP-dependent, Ca(2+)-activated, and delayed rectifier K+ channel activity; (2) RX871024 causes mobilization of Ca2+ from thapsigargin-sensitive intracellular stores, the effect probably controlled by cytochrome P450; and (3) the stimulatory activity of RX871024 on insulin release involves interaction of the compound with the exocytotic machinery, unrelated to the changes in membrane potential and cytoplasmic-free Ca2+ concentration, whereas protein phosphorylation plays an important role in this process.

Effects of imidazoline derivative RX871024 on insulin, glucagon, and somatostatin secretion from isolated perfused rat pancreas.

The effects of the imidazoline compound RX871024 on arginine-induced insulin, glucagon, and somatostatin secretion in the isolated perfused rat pancreas have been investigated. Arginine induced biphasic insulin, glucagon, and somatostatin release when infused for 20 min at 20 mM concentration and 3.3 mM glucose in the medium.

Secretory, biosynthetic and cationic responses to 2-(N-PHENYL-INDOYL)IMIDAZOLE in rat pancreatic islets.

The secretory, biosynthetic and cationic effects of a novel insulinotropic agent with an imidazoline structure, 2-(N-phenyl-indoyl)imidazole hydrochloride (RX 871024) was investigated in rat pancreatic islets. In the 1.0-10-microM range, this agent augmented, in a concentration-related manner, the release of insulin from islets incubated at intermediate concentrations of d-glucose (4.

Influence of different dietary salts on the cardiovascular and renal effects of moxonidine in spontaneously hypertensive rats.

The influence of common salt (NaCl) and a novel potassium-, magnesium-, and L-lysine-enriched mineral salt on the cardiovascular and renal effects of the selective imidazoline I1-receptor agonist moxonidine was examined in spontaneously hypertensive rats (SHR). Common salt was added at the level of 6% of the dry weight of the chow, and mineral salt at a 75% higher level of 10.5% thereof to produce the same NaCl concentration of 6% as in the common salt group.

Investigations of the mechanism of the positive inotropic action of BDF 9148: comparison with DPI 201-106 and the enantiomers.

The electromechanical and biochemical activities of the positive inotropic compounds BDF 9148 and DPI 201-106 were compared in guinea-pig myocardic preparations. Additionally, the properties of the BDF 9148 enantiomers were studied to compare their positive inotropic effects. In guinea pig papillary muscles, BDF 9148 exerted a concentration-dependent increase of force of contraction with a 50% effective concentration (EC50) value of 0.

Why imidazoline receptor modulator in the treatment of hypertension?

The influence of the sympathetic nervous system on blood pressure control was impressively demonstrated in 1940 by bilateral excision of sympathetic nerve fibers. Thereafter, the first generation of drugs lowering blood pressure by central modulation of the sympathetic outflow through alpha 2-adrenoceptor for stimulation, such as alpha-methyldopa, guanabenz, clonidine, and guanfacine, were marketed. However, these compounds were often tolerated poorly, because they caused orthostatic hypotension, sedation, tachycardia or bradycardia, dry mouth, and reduced cardiac output.

Antiarrhythmic effect of the selective I1-imidazoline receptor modulator moxonidine on ouabain-induced cardiac arrhythmia in guinea pigs.

Moxonidine is a centrally acting antihypertensive agent with potent action on I1-imidazoline receptors. Moxonidine as an SIR modulator elicits a persistent reduction in circulating levels of epinephrine, demonstrating a reduction in sympathetic tone. In the first experiment the threshold dose of ouabain needed to induce ventricular arrhythmia and asystole was determined in guinea pigs, and the influence of moxonidine was tested.

Relevance of mediators to cardiac parameters of isolated anaphylactic guinea-pig heart.

The release of histamine, eicosanoids and catecholamines were measured after induction of anaphylaxis in isolated guinea-pig hearts. The concentration-time profile of these mediators was compared with changes of cardiac parameters. The histamine and catecholamine levels of the coronary effluent were determined at 10 s intervals; thromboxane and prostacyclin levels at 60 s intervals.

Is the antiatherosclerotic potency of HDL modulated by the origin of HDL?

Different HDL preparations from rabbit blood were injected intravenously (10 mg HDL protein/injection and animal) into cholesterol fed rabbits twice a week for 8 weeks. The composition of the used high density lipoprotein (HDL) was modified by dietary pretreatment. HDL-1 was taken from rabbits after 8 weeks pellet diet, HDL-2 after 8 weeks fish-oil rich diet and HDL-3 after 8 weeks of cholesterol rich diet.