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

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• 作者：Jadwiga Handzlik^a ; ^{jhandzli@cm-uj.krakow.pl" class="auth_mail} ; ^{j.handzlik@uj.edu.pl" class="auth_mail} ; Andrzej J. Bojarski^b ; Grzegorz Sata艂a^b ; Monika Kubacka^c ; Bassem Sadek^d ; Abrar Ashoor^d ; Agata Siwek^e ; Ma艂gorzata Wi臋cek^a ; Katarzyna Kucwaj^a ; Barbara Filipek^c ; Katarzyna Kie膰-Kononowicz^a
• 关键词：Phenylpiperazines ; Hydantoins ; Mitsunobu reaction ; 5-HT1A ; 5-HT3A ; 5-HT6 ; 5-HT7 ; Alpha1-adrenoceptor
• 刊名：European Journal of Medicinal Chemistry
• 出版年：6 May, 2014
• 年：2014
• 卷：78
• 期：Complete
• 页码：324-339
• 全文大小：964 K

文摘

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-HT₇ and 伪₁-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 伪₁-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for 伪₁-ARs, 5-HT_1A, 5-HT₇ (K_i聽鈭悸?.8-353聽nM) significantly higher than those for 5-HT₆ receptors. Very weak inhibitory effect at 5-HT_3A accompanied with high activity at 伪_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聽=聽3聽nM and selectivity with 40-3600 fold towards 5-HT_1A, 5-HT₆, and 伪₁-ARs.