Evidence that the novel imidazoline compound FT005 is an α 2 ‐adrenoceptor agonist

The aim of this study was to determine whether the hyperglycaemic action of the novel imidazoline compound FT005 could be mediated by activation of α 2 ‐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 K ATP channel opener diazoxide (25 mg kg −1 ). The hyperglycaemic effect of FT005 (1 mg kg −1 ) was significantly reduced by the α 2 ‐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 α 2 ‐adrenoceptors. In radioligand binding studies FT005 completely displaced the α 2 ‐adrenoceptor antagonist [ 3 H]‐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 α 2 ‐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