FT-005

The aim of this study was to determine whether the hyperglycaemic action of the novel imidazoline compound FT005 could be mediated by activation of α2‐adrenoceptors, using a variety of in vivo and in vitro methods including radioligand binding.FT005 produced a dose‐dependent increase in blood glucose levels of CBA/Ca mice (0.125–25 mg kg−1, i.p.). The time course of this hyperglycaemic effect matched that of adrenaline (1 mg kg−1) more closely than glucagon (1 mg kg−1) or the KATP channel opener diazoxide (25 mg kg−1). The hyperglycaemic effect of FT005 (1 mg kg−1) was significantly reduced by the α2‐adrenoceptor antagonist rauwolscine (0.5 mg kg−1).FT005 produced a significant reduction in plasma insulin levels of mice 30 min after administration. The hyperglycaemic effect of FT005 (25 mg kg−1), although still present, was significantly less in fasted mice in which insulin levels are lower, suggesting that a reduction of insulin secretion contributes to the action of FT005.When studied in the mouse isolated vas deferens preparation, FT005 produced a complete inhibition of neurogenic contractions, which was blocked by rauwolscine. This is consistent with activation of pre‐synaptic α2‐adrenoceptors.In radioligand binding studies FT005 completely displaced the α2‐adrenoceptor antagonist [3H]‐RX821002 from mouse whole brain homogenates. The displacement was best described by a two‐site model of interaction comprising high and low affinity components.The results indicate that FT005 is an agonist at α2‐adrenoceptors. A reduction in insulin secretion contributes to the hyperglycaemic action of FT005, although an additional mechanism can not be excluded.British Journal of Pharmacology (2002) 136, 1049–1057. doi:10.1038/sj.bjp.0704810