Subclassification of α1‐adrenoceptor recognition sites by urapidil derivatives and other selective antagonists

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Abstract
The affinities of urapidil derivatives and other antagonists for α1‐adrenoceptors labelled by [3H]‐prazosin were determined on membranes of six different rat tissues. Urapidil and its 5‐acetyl‐, 5‐formyl‐ and 5‐methyl‐derivative displaced [3H]‐prazosin from α1‐adrenoceptor binding sites in a concentration‐dependent manner which varied with tissue. IC50 values were lower in vas deferens, hippocampus and cerebral cortex than in heart, liver and spleen. For 5‐methyl‐urapidil, binding to two distinct sites could be demonstrated with mean K1 values of about 0.6 and 45 nM. Saturation binding studies with [3H]‐prazosin in the presence of 5‐methylurapidil indicated a competitive type of interaction between 5‐methyl‐urapidil and [3H]‐prazosin. The proportion of [3H]‐prazosin binding sites with high affinity for 5‐methyl‐urapidil was 58% in vas deferens, 69% in hippocampus, 41% in cerebral cortex and 23% in myocardium. In liver and spleen virtually no high affinity sites were found. These values were in good agreement with the percentages of binding sites with high affinities for WB‐4101 and phentolamine, indicating that all these antagonists bind to the same subtype of α1 ‐recognition sites, whereas other α‐antagonists like BE 2254, yohimbine and unlabelled prazosin did not discriminate between two binding sites. Preincubating membranes of the cerebral cortex with chloroethylclonidine preferentially inactivated [3H]‐prazosin binding sites with low affinity for 5‐methyl‐urapidil. The antagonist potencies of 5‐methyl‐urapidil and WB‐4101 against α1‐adrenoceptor‐mediated contractile responses were higher in vas deferens than in myocardium. The α1‐mediated effects in vas deferens but not in the heart were highly susceptible to nitrendipine. Using 5‐methyl‐urapidil, the existence of two distinct α1‐adrenoceptor recognition sites could be demonstrated which correspond to the proposed α1A‐ and α1B‐subtypes. Since 5‐methyl‐urapidil is one of the ligands with most selectivity between these subtypes in binding studies it may serve as a valuable tool for such investigations.