5193-50-0Relevant academic research and scientific papers
New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT7and 5-HT1Areceptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies
Intagliata, Sebastiano,Modica, Maria N.,Pittalà, Valeria,Salerno, Loredana,Siracusa, Maria A.,Cagnotto, Alfredo,Salmona, Mario,Kurczab, Rafa?,Romeo, Giuseppe
, p. 1250 - 1259 (2017)
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-HT7and 5-HT1Areceptors. 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-HT7and 5-HT1Areceptors, 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-HT7and 6.96 and 2.99?nM for 5-HT1Areceptors, 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-HT7and 5-HT1Areceptor 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.
