Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α₁-Adrenoceptor Subtypes

Abstract

Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant α₁-adrenoceptor subtypes (α_1a-, α_1b- and α_1d-subtypes) were examined and compared with the functional affinities obtained in rat caudal artery (α_1A-subtype), dog carotid artery (α_1B-subtype) and rat thoracic aorta (α_1D-subtype). Most of the 5-HT-receptor antagonists and agonists tested showed relatively high affinity to three α₁-adrenoceptor subtypes. The highest affinity close to 1 nM was seen for NAN-190 (5-HT_1A antagonist) in binding and functional studies. 5-Methylurapidil (5-HT_1A agonist) and BMY7378 (5-HT_1A agonist) showed, respectively, α_1a(α_1A)- or α_1d(α_1D)-subtype selectivity in both binding and functional affinities, but spiperone (5-HT_2A antagonist) showed α_1b-selectivity only in binding affinity. Functional affinity of ritanserin (5-HT_2A antagonist) to the α_1B-subtype was approximately 500-fold lower than that of affinity to the α_1b-subtype. The present results show that many 5-HT-receptor antagonists and agonists have high affinity to α₁-adrenoceptors, but suggest that there is deviation between their functional affinities and binding affinities for some drugs.