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New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT 7 and 5-HT 1A receptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Feb 01; Vol. 25 (3), pp. 1250-1259. Date of Electronic Publication: 2016 Dec 27. - Publication Year :
- 2017
-
Abstract
- 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-HT <subscript>7</subscript> and 5-HT <subscript>1A</subscript> 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-HT <subscript>7</subscript> and 5-HT <subscript>1A</subscript> 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, K <subscript>i</subscript> =23.5 and 8.42nM for 5-HT <subscript>7</subscript> and 6.96 and 2.99nM for 5-HT <subscript>1A</subscript> 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-HT <subscript>7</subscript> and 5-HT <subscript>1A</subscript> 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.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Dose-Response Relationship, Drug
HEK293 Cells
Humans
Ligands
Models, Molecular
Molecular Structure
Pyrimidines chemical synthesis
Pyrimidines chemistry
Quinazolines chemical synthesis
Quinazolines chemistry
Structure-Activity Relationship
Pyrimidines pharmacology
Quinazolines pharmacology
Receptor, Serotonin, 5-HT1A metabolism
Receptors, Serotonin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 25
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28063784
- Full Text :
- https://doi.org/10.1016/j.bmc.2016.12.039