5-HT2 antagonist activity of 3-aminomethyltetralones

Bioorganic & Medicinal Chemistry Letters
1991.0

Abstract

In this letter we report the affinity of the above compounds for 5-HT2 receptors, as measured by their inhibition of [3H]-ketanserine binding to frontal cerebral cortex membranes of rat (15), together with their inhibitory activity against serotonin-induced contractions in rat aorta rings stripped of endothelium (11-14). All four compounds were active. The most active was compound 4, which had a pA2 slightly lower than that of ketanserin in the aorta-rings experiments and a pKi similar to that of methysergide in the binding experiments. Compounds 2 and 3, which have p-fluoro-4 aminobutyrophenone moieties instead of the p-fluoro-4benzoylpiperidine moiety of 4, were less active than the latter, while compound 1, which has an o-methoxyphenylpiperazinyl moiety, was only moderately active. The significant activities of compounds 2 and 3, though 20 times lower than those of ketanserin and methysergide, suggest that their tetralone moieties contributed to antagonism of serotonin at 5-HT2 receptors. The most active compound, the pfluoro4benzoylpiperidine derivative 4, whose inhibition of ketanserin binding to 5-HT2 receptors was similar to that of methysergide, has been selected for further investigation under the code number QF0104B.

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