TY - JOUR
T1 - New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT7 and 5-HT1A receptor ligands
T2 - Synthesis, structure-activity relationships, and molecular modeling studies
AU - Intagliata, Sebastiano
AU - Modica, Maria N
AU - Pittalà, Valeria
AU - Salerno, Loredana
AU - Siracusa, Maria A
AU - Cagnotto, Alfredo
AU - Salmona, Mario
AU - Kurczab, Rafał
AU - Romeo, Giuseppe
N1 - Copyright © 2016 Elsevier Ltd. All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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 8.42nM for 5-HT7 and 6.96 and 2.99nM 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.
AB - 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 8.42nM for 5-HT7 and 6.96 and 2.99nM 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.
KW - Dose-Response Relationship, Drug
KW - HEK293 Cells
KW - Humans
KW - Ligands
KW - Models, Molecular
KW - Molecular Structure
KW - Pyrimidines
KW - Quinazolines
KW - Receptor, Serotonin, 5-HT1A
KW - Receptors, Serotonin
KW - Structure-Activity Relationship
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.bmc.2016.12.039
DO - 10.1016/j.bmc.2016.12.039
M3 - Article
C2 - 28063784
VL - 25
SP - 1250
EP - 1259
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 3
ER -