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Evidence that the multiflorine-derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at ?2 -adrenoceptors in mice.
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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?-1 *30?min-1 : without ?2 -adrenoceptor agonist: 500??mol/L 55P0251, 390?±?34, vs 55P0250, 459?±?40, nonsignificant; with ?2 -adrenoceptor agonist: 250??mol/L 55P0251, 138?±?9, vs 55P0250, 21?±?6; P?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 ?2 -antagonistic action in vivo (90?mg/kg 55P0251, 83?±?3%, vs 55P0250, 57?±?3%; P?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 ?2 -adrenoceptor antagonists with potential to lower blood glucose by blocking ?2A -adrenoceptors on pancreatic ? cells.
SUBMITTER: Lehner Z
PROVIDER: S-EPMC7065191 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Publications
Evidence that the multiflorine-derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α<sub>2</sub> -adrenoceptors in mice.
Diabetes, obesity & metabolism 20191107 3
<h4>Aims</h4>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.<h4>Materials and methods</h4>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 inve ...[more]
