New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT₇ and 5-HT_1A receptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies

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• 作者：Sebastiano Intagliata^a ; ¹ ; ^{s.intagliata@studium.unict.it} ; Maria N. Modica^a ; ¹ ; Valeria Pittalà ; ^a ; Loredana Salerno^a ; Maria A. Siracusa^a ; Alfredo Cagnotto^b ; Mario Salmona^b ; Rafał Kurczab^c ; Giuseppe Romeo^a
• 关键词：5-HT7 receptor ligands ; 5-HT1A receptor ligands ; Long-chain arylpiperazines ; Molecular modeling
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1250-1259
• 全文大小：1666 K
• 卷排序：25

文摘

Based on our earlier studies of structure activity relationships on 4-substituted piperazine derivatives, in this work we synthesized a novel set of long-chain arylpiperazines with the purpose of elucidating if some structural modifications in the terminal fragment could affect the binding affinity for the 5-HT7 and 5-HT1A receptors. In this new series, the quinazolinone system of the previous derivatives was replaced by a 6-phenylpyrimidine or a 2-methylquinazoline, which were used as versatile building blocks for the preparation of new compounds. A 4-arylpiperazine moiety through a five methylene chain was anchored at the nitrogen or oxygen atom of the heterocyclic scaffolds. The substituents borne by the piperazine nucleus were phenyl, phenylmethyl, 3- or 4-chlorophenyl, and 2-ethoxyphenyl. Binding tests, performed on human cloned 5-HT7 and 5-HT1A receptors, showed that, among the newly synthesized derivatives, 4-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentoxy]-6-phenyl-pyrimidine (13) and 3-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentyl]-2-methyl-4(3H)-quinazolinone (20) displayed the best affinity values, Ki = 23.5 and 8.42 nM for 5-HT7 and 6.96 and 2.99 nM for 5-HT1A receptors, respectively. Moreover, the functional properties for both compounds were further evaluated using the cAMP assay. Finally, a molecular modeling study has been performed for 5-HT7 and 5-HT1A receptor homology models to investigate the binding mode of N- and O-alkylated pyrimidinones/pyrimidines 4–13, 2-methylquinazolinones/quinazolines 17–22, and previously reported 2- and 3-substituted quinazolinones 23–30.