ABSTRACT-Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant a1-adrenoceptor subtypes (a 1a-, a1b-and a1d-subtypes) were examined and compared with the functional affinities obtained in rat caudal artery (a1A-subtype), dog carotid artery (a1B-subtype) and rat thoracic aorta (=1D-subtype). Most of the 5-HT-receptor antagonists and agonists tested showed relatively high affinity to three a 1-adrenoceptor subtypes. The highest affinity close to 1 nM was seen for in binding and functional studies. 5-Methylurapidil (5-HT1A agonist) and BMY7378 (5-HT1A agonist) showed, respectively, a 1a(a 1A)-or a1d(a1D)-subtype selectivity in both binding and functional affinities, but spiperone (5-HT2A antagonist) showed a1b-selectivity only in binding affinity. Functional affinity of ritanserin (5-HT2A antagonist) to the a1B-subtype was approximately 500-fold lower than that of affinity to the =1b-subtype. The present results show that many 5-HT-receptor antagonists and agonists have high affinity to a1-adrenoceptors, but suggest that there is deviation between their functional affinities and binding affinities for some drugs.Keywords: Serotonin receptor antagonist, Serotonin receptor agonist, a 1-Adrenoceptor, Selectivity a1-Adrenoceptors comprise a heterogeneous family (1 -3). Molecular biological studies have provided evidence for the existence of at least three genes encoding a1a-, a1b-and a1d-adrenoceptors (with lowercase letters) that correspond to the pharmacologically defined native a1A-, a1B-and a 1D-adrenoceptors (with uppercase letters) (4, 5). Pharmacological studies have revealed several subtypeselective agents: for example, 5-methylurapidil, KMD-3213, RS-17053 and nigludipine for the a1a-subtype (6 -9); spiperone for the a1b-subtype (10); and BMY7378 for the a1d-subtype (11, 12). Among them, 5-methylurapidil, spiperone and BMY7378 were originally categorized in serotonin (5-HT) receptor agonists and / or antagonists.Many 5-HT receptor antagonists have been developed and some of them are now clinically used as anticoagulants, antihypertensive drugs and antipsychotic drugs (13,14). Such therapeutic diversity of 5-HT antagonists may be related to their wide spectrum for not only 5-HT receptor family but also for heterogeneous receptors such as dopamine receptors and a1-adrenoceptors (15, 16).The present study was undertaken to examine the possible selectivity for a1-adrenoceptor subtypes of 5-HT receptor agonists and antagonists including clinically active antipsychotic drugs. The selectivity was evaluated with two parameters: binding affinity to recombinant human a 1a-, a1b-and a1d-adrenoceptors expressed in Chinese hamster ovary (CHO) cells and functional affinity to native a1A-(rat caudal artery) (17), a 1B-(dog carotid artery) (18,19) and a 1D-(rat thoracic aorta) (20) adrenoceptors. A good relationship was already reported for a 1-adrenoceptorselective drugs between the recombinant and native a1-adrenoceptors (7, 21). MATERIALS AND METHODS Membrane preparation and radiolig...