Evidence that the novel imidazoline compound FT005 is an alpha(2)-adrenoceptor agonist.

1: The aim of this study was to determine whether the hyperglycaemic action of the novel imidazoline compound FT005 could be mediated by activation of alpha(2)-adrenoceptors, using a variety of in vivo and in vitro methods including radioligand binding. 2: 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 alpha(2)-adrenoceptor antagonist rauwolscine (0.5 mg kg(-1)). 3: 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. 4: 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 alpha(2)-adrenoceptors. 5: In radioligand binding studies FT005 completely displaced the alpha(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. 6: The results indicate that FT005 is an agonist at alpha(2)-adrenoceptors. A reduction in insulin secretion contributes to the hyperglycaemic action of FT005, although an additional mechanism can not be excluded.

Effects of the imidazoline ligands efaroxan and KU14R on blood glucose homeostasis in the mouse.

The putative imidazoline I(3) receptor antagonist 2-(2-ethyl-2,3-dihydrobenzo[b]furan-2-yl)-1H-imidazole (KU14R) has been shown to block the effects of the atypical I(3) agonist efaroxan at the level of the ATP-sensitive K(+) (K(ATP)) channel in isolated pancreatic islet beta cells, but its effects in vivo are not known. We have therefore investigated the effects of KU14R on blood glucose and insulin level in vivo. When KU14R was administered before or after a hypoglycaemic dose of efaroxan, the fall in blood glucose was at least additive. When the antihyperglycaemic imidazoline ligand S22068 was administered after a dose of KU14R, it did not alter the hypoglycaemic response. In the mouse isolated vas deferens preparation, neither rauwolscine (at concentrations which competitively antagonised the inhibitory response to 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK14304)) nor KU14R affected inhibition produced by S22068. At 10(-4) M, KU14R had weak alpha(2)-adrenoceptor antagonist activity. We conclude that KU14R does not act as an antagonist of either efaroxan or S22068 at an imidazoline site in vivo.