Dissection of mechanisms that account for imidazoline-induced lowering of blood glucose in mice

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

“…In this setting, a low dose of 1 mg/kg 55P0251 potently counteracted hyperglycaemia induced by an α 2 ‐adrenoceptor agonist as well as hyperglycaemia induced by a K ATP channel‐opener, suggesting that 55P0251, like other α 2A ‐adrenoceptor antagonists, addresses both mechanisms (Figure B). It is notable, however, that 55P0251 was relatively potent in counteracting hyperglycaemia caused by K ATP channel‐opening (reduction of incremental AUC diazoxide, −37.4 ± 2.7%, vs induced by UK14,304, −14.8 ± 4.7%; P = .012), which distinguished 55P0251 from other α 2A ‐adrenoceptor antagonists and extended previous observations of relevant variation in the molecular pharmacology of individual α 2A ‐adrenoceptor antagonists (Figure S1) …”

“…While non-adrenergic action(s) obviously include direct interaction with K ATP channels on β cells, 29-32 the potency of a given α 2A -adrenoceptor antagonist as K ATP channel blocker is not necessarily proportional to its potency at the adrenoceptor, which presumably contributes to variability among the pharmacological profiles of individual compounds. 13,14 With regard to our novel structures, an adrenoceptor-independent mechanism could explain enantiomer-independent stimulation of insulin release in the absence of α 2 -adrenoceptor agonists from isolated islets, as we observed it at high concentrations of 55P0251 and 55P0250 ( Figure 2B). We then exploited a previously applied protocol for the dissection of contributions of adrenoceptor versus K ATP channel-mediated effects on blood glucose in vivo.…”

“…In addition, many α 2A ‐adrenoceptor antagonists are known to modulate insulin release not only via adrenoceptors, but also via one (or even more) non‐adrenergic mechanism(s). While non‐adrenergic action(s) obviously include direct interaction with K ATP channels on β cells, the potency of a given α 2A ‐adrenoceptor antagonist as K ATP channel blocker is not necessarily proportional to its potency at the adrenoceptor, which presumably contributes to variability among the pharmacological profiles of individual compounds …”

“…With regard to our novel structures, an adrenoceptor‐independent mechanism could explain enantiomer‐independent stimulation of insulin release in the absence of α 2 ‐adrenoceptor agonists from isolated islets, as we observed it at high concentrations of 55P0251 and 55P0250 (Figure B). We then exploited a previously applied protocol for the dissection of contributions of adrenoceptor versus K ATP channel‐mediated effects on blood glucose in vivo . In this setting, a low dose of 1 mg/kg 55P0251 potently counteracted hyperglycaemia induced by an α 2 ‐adrenoceptor agonist as well as hyperglycaemia induced by a K ATP channel‐opener, suggesting that 55P0251, like other α 2A ‐adrenoceptor antagonists, addresses both mechanisms (Figure B).…”

“…We then exploited a previously applied protocol for the dissection of contributions of adrenoceptor versus K ATP channel-mediated effects on blood glucose in vivo. 13,14 In this setting, a low dose of 1 mg/kg Figure S1). 13,14 In conclusion, without any postulation of a molecular mechanism at work we have discovered and developed a novel class of fully synthetic substituted quinazolidines, which shows distinct antihyperglycaemic activity in mice.…”