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.
Slough
Scott
S
Department of Pharmacology, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Guillaumet
Gerald
G
Taberner
Peter V
PV
D000284:Administration, Oral; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009025:Morpholines / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D013997:Time Factors; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D015016:Yohimbine / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; C472556:FT 005; D007093:Imidazoles; D007328:Insulin; D009025:Morpholines; D015016:Yohimbine