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Aims: To investigate the mechanism of action of 55P0251, a novel multiflorine-derived substituted quinazolidine that augments insulin release and lowers blood glucose in rodents, but does not act via mechanisms addressed by any antidiabetic agent in clinical use., Materials and Methods: Using male mice, we determined the effects of 55P0251 on glucose tolerance, insulin secretion from isolated islets and blood oxygen saturation, including head-to-head comparison of 55P0251 to its inverted enantiomer 55P0250, as well as to other anti-hyperglycaemic multiflorine derivatives discovered in our programme., Results: 55P0251 was clearly superior to its inverted enantiomer in the glucose tolerance test (area under the curve: 11.3 mg/kg 55P0251, 1.19 ± 0.04 min*mol/L vs 55P0250, 1.80 ± 0.04 min*mol/L; P < .0001). For insulin release in vitro, this superiority became visible only under concomitant adrenergic background stimulation (glucose-stimulated insulin release, fmol*islet -1 *30 min -1 : without α 2 -adrenoceptor agonist: 500 μmol/L 55P0251, 390 ± 34, vs 55P0250, 459 ± 40, nonsignificant; with α 2 -adrenoceptor agonist: 250 μmol/L 55P0251, 138 ± 9, vs 55P0250, 21 ± 6; P < .0001). Since receptor binding assays suggested antagonism at α 2A -adrenoceptors as a potential mechanism of action, we measured oxygen saturation in capillary blood from the tail as a surrogate of vasoconstriction, which supported α 2 -antagonistic action in vivo (90 mg/kg 55P0251, 83 ± 3%, vs 55P0250, 57 ± 3%; P < .0001). Lack of association between glucose-lowering activities and α 2A -adrenoceptor binding affinity arising from comparison of multiflorine derivatives was attributed to differences in their pharmacokinetic properties., Conclusions: Our findings suggest that 55P0251 and related multiflorine derivatives are to be categorized as α 2 -adrenoceptor antagonists with potential to lower blood glucose by blocking α 2A -adrenoceptors on pancreatic β cells., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Two mechanisms have been proposed for the modulation of skeletal muscle glucose metabolism by amino acids. Whereas studies on humans and cultured cells suggested acute insulin desensitization via mammalian target of rapamycin (mTOR) and its downstream target p70 S6 kinase (S6K), investigations using native specimens of rat muscle hinted at impairment of glucose oxidation by competition for mitochondrial oxidation. To better understand these seemingly contradictory findings, we explored the effects of high concentrations of mixed amino acids on fuel metabolism and S6K activity in freshly isolated specimens of rat skeletal muscle. In this setting, increasing concentrations of amino acids dose-dependently reduced the insulin-stimulated rates of CO(2) production from glucose and palmitate (decrease in glucose oxidation induced by addition of 5.5, 11, 22, and 44 mmol/l amino acids:--16 +/- 3, -25 +/- 7, -44 +/- 4, -62 +/- 4%; P < 0.02 each). This effect could not be attributed to insulin desensitization, because it was not accompanied by any reduction of insulin-stimulated glucose transport [+12 +/- 16, +17 +/- 22, +21 +/- 33, +13 +/- 12%; all nonsignificant (NS)] or glycogen synthesis (+1 +/- 6, -5 +/- 6, -9 +/- 8, +6 +/- 5%; all NS) and because it persisted without insulin stimulation. Abrogation of S6K activity by the mTOR blocker rapamycin failed to counteract amino acid-induced inhibition of glucose and palmitate oxidation, which therefore was obviously independent of mTOR/S6K signaling (decrease in glucose oxidation by addition of 44 mmol/l amino acids: without rapamycin, -60 +/- 4%; with rapamycin, -50 +/- 13%; NS). We conclude that amino acids can directly affect muscle glucose metabolism via two mechanisms, mTOR/S6K-mediated insulin desensitization and mitochondrial substrate competition, with the latter predominating in isolated rat muscle.

Aims 55P0251 is a novel compound with blood glucose lowering activity in mice, which has been developed from a molecular backbone structure found in herbal remedies. We here report its basic pharmacological attributes and initial progress in unmasking the mode of action. Materials and methods Pharmacokinetic properties of 55P0251 were portrayed in several species. First efforts to elucidate the glucose lowering mechanism in rodents included numerous experimental protocols dealing with glucose tolerance, insulin secretion from isolated pancreatic islets and comparison to established drugs. Results A single oral dose of 55P0251 improved glucose tolerance in mice with an ED50 between 1.5 and 2 mg/kg (reductions in areas under the curve, 1 mg/kg, −18%; 5 mg/kg, −30%; 27 mg/kg, −47%). Pharmacokinetic studies revealed attractive attributes, including a plasma half-life of approximately 3 hours and a bioavailability of approximately 58% in rats. 55P0251 amplified glucose stimulated insulin release from isolated mouse islets and improved glucose tolerance via increased insulin secretion in rats (increase in area under the insulin curve, +184%). Unlike sulfonylureas and glinides, 55P0251 hardly stimulated insulin release under basal conditions and did not induce hypoglycaemia in vivo, but it amplified the secretory response to glucose and other insulinotropic stimuli ( KCl, glucagon-like peptide-1). Comparison to established anti-diabetic agents and examination of interaction with molecular targets ( KATP channel, dipeptidyl peptidase-4, glucagon-like peptide-1 receptor) excluded molecular mechanisms addressed by presently marketed drugs. Conclusions 55P0251 is a novel compound that potently counteracts hyperglycaemia in rodents via amplification of glucose-stimulated insulin release. [ABSTRACT FROM AUTHOR]