SAR-studies on the importance of aromatic ring topologies in search for selective 5-HT₇ receptor ligands among phenylpiperazine hydantoin derivatives

The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer-Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT_1A, 5-HT₆, 5-HT ₇ and α₁-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT_3A expressed in Xenopus Oocytes as well as on their activity at α₁-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α₁-ARs, 5-HT_1A, 5-HT₇ (K_i ∼ 0.8-353 nM) significantly higher than those for 5-HT₆ receptors. Very weak inhibitory effect at 5-HT_3A accompanied with high activity at α_1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl) -5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT₇ affinity with K_i = 3 nM and selectivity with 40-3600 fold towards 5-HT_1A, 5-HT₆, and α₁-ARs.