Evidence that the multiflorine-derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α2 -adrenoceptors in mice

Abstract

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 α₂ -adrenoceptor agonist: 500 μmol/L 55P0251, 390 ± 34, vs 55P0250, 459 ± 40, nonsignificant; with α₂ -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 α₂ -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 α₂ -adrenoceptor antagonists with potential to lower blood glucose by blocking α_2A -adrenoceptors on pancreatic β cells.

Keywords: animal pharmacology; antidiabetic drug; drug development; drug mechanism; insulin secretion.