Alpha-1 and alpha-2 adrenoceptor binding in cerebral cortex: Competition studies with [3H]prazosin and [3H]idazoxan

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Abstract
The tritiated adrenergic antagonists prazosin ([3H]PRZ) and idazoxan ([3H]IDA, or RX-781094) bind specifically and with high affinity in membrane preparations from cerebral cortex to alpha-1- and alpha-2-adrenoceptors respectively. Saturation experiments, performed to determine the density of receptors (Bmax; maximum binding capacity) and the dissociation constant (Kd 25 °C), were analyzed by the methods of Eadie and Hofstee, iterative modelling, and the procedure of Hill. The pharmacologic properties and specificity of the labelling was verified by displacement experiments using alpha-adrenergic antagonists and agonists. The antagonist drugs showed the following order of potency to displace [3H]prazosin: prazosin ≫ phentolamine ≫ corynanthine > pyrextramine ≫ yohimbine ≫ piperoxan > benextramine > idazoxan; for the agonists: clonidine ≫ (−)-noradrenaline ≫ (−)-adrenaline ≫ phenylephrine, while other drugs, such as (−)-propranolol, dopamine, (−)-isoproterenol and serotonin only competed with the alpha-1-ligand at concentrations above 20 μM. The alpha2-sites labelled by [3H]idazoxan were characterized by the antagonist displacement sequence idazoxan ≫ phentolamine > yohimbine = > piperoxan ≫ pyrextramine ≫ benextramine ≫ prazosin ≫ corynanthine. The agonists order of potency to compete with [3H]idazoxan was clonidine ≫ phenylephrine = > (−)-adrenaline > (−)-noradrenaline, and for other related drugs it was (−)-propranolol ≫ dopamine ≫ serotonin > (−)-isoproterenol. These competition experiments clearly showed two pharmacologically distinct sites, but question the relative specificity of some of the adrenergic drugs.