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

Article abstract of DOI:10.1016/j.ejmech.2014.01.065

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.