title: New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT7and 5-HT1Areceptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies.
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-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 8.42nM for 5-HT7and 6.96 and 2.99nM 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.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, viale A. Doria 6, Catania 95125, Italy. Electronic address: s.intagliata@studium.unict.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Intagliata
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, viale A. Doria 6, Catania 95125, Italy.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Modica
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, viale A. Doria 6, Catania 95125, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, viale A. Doria 6, Catania 95125, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, viale A. Doria 6, Catania 95125, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Siracusa
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, Milano 20156, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, Milano 20156, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Kurczab
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, viale A. Doria 6, Catania 95125, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
mesh_terms: D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011743:Pyrimidines; D011799:Quinazolines; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT(1A) receptor ligands; 5-HT(7) receptor ligands; Long-chain arylpiperazines; Molecular modeling