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 alpha 2-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 alpha 2-adrenoceptors both presynaptically as well as postsynaptically. SL 84.0418 is a novel alpha 2-adrenoceptor antagonist with preferential effects in the periphery and with at least a 10-fold higher selectivity ratio between alpha 2 and alpha 1-adrenoceptors when compared with idazoxan. SL 84.0418 antagonizes the hyperglycemia and the inhibition of insulin release induced by the alpha 2-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.