In order to search for active and selective serotonin 5-HT<sub>7</sub>R antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione (<b>2</b>, KKB16) were performed. New derivatives (<b>4-18</b>) were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione (<b>3</b>) was performed to support molecular modeling and SAR studies. The affinity for 5-HT<sub>7</sub>R, D<sub>2</sub>R and 5-HT<sub>1A</sub>R in radioligand binding assays for the entire series and ADME-Tox parameters <i>in vitro</i> for selected compounds (<b>7</b>, <b>10</b>, and <b>13</b>) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HT<sub>7</sub>R agents (<i>K</i><sub>i</sub> ≤ 5 nM) with significant selectivity over 5-HT<sub>1A</sub>R and D<sub>2</sub>R. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HT<sub>7</sub>R/5-HT<sub>1A</sub>R action (<i>K</i><sub>i</sub>: 11 nM/19 nM).