title: Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT(7) and 5-HT(1A) receptor ligands.
abstract: A novel series of arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones 18-38 was designed, synthesized and tested to evaluate their affinity for the 5-HT7 and 5-HT1A receptors. Compounds with a 2-benzothiazolone nucleus generally had affinity values higher than the corresponding 2-benzoxazolone compounds. In particular, derivatives possessing a six or seven carbon chain linker between 2-benzothiazolone and arylpiperazine had Ki values in the subnanomolar range for the 5-HT1A receptor and in the low nanomolar range for the 5-HT7 receptor, indicating that they may be interesting dual ligands. Molecular modeling studies revealed different docking poses for the investigated compounds in homology models of 5-HT1A and 5-HT7 receptors, which explained their experimentally determined affinities and general low selectivity. Additionally, structural interaction fingerprints analysis identified the important amino acid residues for the specific interactions of long-chain arylpiperazines within the binding pockets of both serotonin receptors.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: mmodica@unict.it.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Modica
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Siracusa
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Intagliata
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Kurczab
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry* / Q000378:metabolism*; D001583:Benzoxazoles / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D001583:Benzoxazoles; D008024:Ligands; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A; C017057:benzoxazolone; C005465:benzothiazole
keywords: 5-HT(1A); 5-HT(7); LCAP; Ligands; Receptors; Serotonin