Abstract
Serotonin (5-HT<sub>2</sub>) antagonists show high affinity for the α<sub>1</sub>-adrenoceptor (α<sub>1</sub>-AR) in addition to the 5-HT<sub>2</sub> receptor. In the present study we compared the pharmacological characteristics of a new 5-HT<sub>2</sub> antagonist sarpogrelate and its active metabolite M-1 with those of ketanserin on human recombinant α<sub>1</sub>-AR subtypes. In the binding study, sarpogrelate, M-1 and ketanserin produced concentration-dependent inhibition of <sup>3</sup>H-prazosin binding to α<sub>1</sub>-ARs. Among the three drugs, ketanserin showed the highest affinity for α<sub>1a</sub>-, α<sub>1b</sub>- and α<sub>1d</sub>-ARs (pKi 8.0, 8.3 and 7.6, respectively). Sarpogrelate had a relatively low affinity for the three subtypes (6.3 , 6.4 and 6.3, respectively) and M-1 showed medium affinity (7.1, 7.1 and 6.1, respectively). Chinese hamster ovary (CHO) cells expressing each α<sub>1</sub>-AR subtype showed concentration-dependent inositol phosphate (IP) accumulation in response to phenylephrine. The concentration response curves were shifted to the right by three drugs, and the pKb values were close to the pKi values in the binding study. In addition to these effects, sarpogrelate and M-1, but not ketanserin produced an increase in the basal IP level of α<sub>1d</sub>-expressed CHO cells, although the increase was less than that of phenylephrine. The present results indicate that sarpogrelate and M-1 have antagonistic activity to the three α<sub>1</sub>-AR subtypes, but their affinities are significantly lower than those of ketanserin.
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