Pre- and postsynaptic alpha-2 adrenoceptors as target for drug discovery
The presynaptic terminal autoreceptors which modulate the release of noradrenaline through a negative feed-back mechanism correspond to the α2-subtype of adrenoceptors. These receptors are also present post- synaptically in the pancreatic islets were they mediate inhibition of the glucose- induced release of insulin. The sympathetic innervation of the pancreatic islets involves α2-adrenoceptors both presynaptically as well as postsynaptically. SL 84.0418 is a novel α2-adrenoceptor antagonist with preferential effects in the periphery and with at least a 10-fold higher selectivity ratio between α2 and ar adrenoceptors when compared with idazoxan. SL 84.0418 antagonizes the hyperglycemia and the inhibition of insulin release induced by the α2- adrenoceptor agonist UK 14304. The administration of SL 84.0418 significantly reduces the glucose evoked hyperglycemia in several species including man. It is proposed that SL 84.0418 may represent a useful and novel hypoglycemic drug in the treatment of type II diabetes.
KeywordsInsulin Release Selectivity Ratio Rabbit Pulmonary Artery Canine Saphenous Vein High Selectivity Ratio
Unable to display preview. Download preview PDF.
- Angel I, Schoemaker H, Azerhad R, Bidet S, Duval N, Langer SZ (1990b) SL 84.0418: a new alpha-2 antagonist with antihyperglycemic and lipolytic activity. Int J Obesity 14 [Suppl 2): 50Google Scholar
- Angel I, Schoemaker H, Arbilla S, Galzin AM, Berry C, Niddam R, Pimoule C, Sevrin M, Wick A, Langer SZ (1991a) SL 84.0418: a novel, potent and selective alpha-2 adrenoceptor antagonist. I. In vitro pharmacological profile. J Pharmacol Exp Ther (submitted)Google Scholar
- Angel I, Grosset A, Perrault G, Schoemaker, H, Langer SZ (1991b) SL 84.0418: a new, potent and selective alpha-2 adrenoceptor antagonist with preferential peripheral activity. I I. In vivo pharmacological profile. J Pharmacol Exp Ther (submitted)Google Scholar
- Duval N, Angel I, Eon MT, Oblin A, Langer SZ (1991) Involvement of alpha-2 and beta-adrenoceptors in insulin release induced by pancreatic nerve stimulation. J Pharmacol Exp Ther (submitted)Google Scholar
- Lafontan M, Berlan M, Carpene C (1985) Fat cell adrenoceptors: inter and intraspecific differences and hormone regulation. Int J Obesity 9 [Suppl]: 117–127.Google Scholar
- Langer SZ (1981) Presynaptic regulation of the release of catecholamines. Pharmacol Rev 32: 337–362Google Scholar
- Minneman KP (1988) α1Adrenergic receptor subtypes, inositol phosphates, and sources of cell Ca2+. Pharmacol Rev 40(2): 87–119Google Scholar
- Schoemaker H, Blanchard H, Pimoule C, Lefevre-Borg F, Manoury, P, Jardin A, Langer SZ (1989) Characterization of the effects of alfuzosin on α1-adrenoceptors in the genito-urinary tract. In: Prostate et Alpha-Bloquants. Excerpta Medica, Amsterdam, pp 328–343Google Scholar