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 α2A‐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 α2A‐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 α2A‐adrenoceptors on pancreatic β cells.

Computational study demonstrated anti-diabetic potencies of Diosgenin and Multiflorenol as peroxisome proliferator-activated receptor gamma agonist

“…Accumulating evidence demonstrated that both diosgenin and multiflorenol exert anti-diabetic abilities (Table 2). Lehner et al 2020 There are several mechanisms how diosgenin and multiflorenol decrease the negative effects of diabetes mellitus. For example, diosgenin could reduce the activity of several biomarkers related to diabetes mellitus such as α-amylase, α-glucosidase (Ghosh et al 2014), andSGLT-1 (Al-Habori et al 2001).…”

New Analytical Approach to Quinolizidine Alkaloids and Their Assumed Biosynthesis Pathways in Lupin Seeds

“…Another important motivation for this effort is the desired biological activity that QAs have demonstrated in multiple studies [ 35 ]. Many QAs show beneficial and desired qualities such as antioxidant, antimicrobial, anti-carcinogenic, and anti-inflammatory activities [ 23 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. However, several individual alkaloids, especially sparteine, anagyrine, and cysteine, have undesired or even toxic activity, thus their concentrations in edible lupins must be strongly regulated [ 4 , 47 ].…”

A Review on the Antidiabetic Potential of Medicinal Plants

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