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.
Department of Biology, Synthélabo Recherche (LERS), Paris, France.
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Langer
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D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D006943:Hyperglycemia / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D019329:Idazoxan; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001381:Azepines; D004146:Dioxanes; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D011758:Pyrroles; D011942:Receptors, Adrenergic, alpha; C074936:SL 84.0418; C015603:azepexole; D009638:Norepinephrine; D019329:Idazoxan