title: Synthesis and structure-activity relationship studies in serotonin 5-HT4 receptor ligands based on a benzo[de][2,6]naphthridine scaffold.
abstract: A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8a-g were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptor-G protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4). The result was rationalized by docking studies in term of high similarity in the binding modalities of flexible 7a and conformationally constrained 8b. The intrinsic efficacy of some selected ligands was determined by evaluating the receptor-G protein coupling and the results obtained demonstrated that the nature and the position of substituents play a critical role in the interaction of these ligands with their receptor.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Castriconi
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Paolino
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: Rottapharm Madaus, Via Valosa di Sopra 9, 20052 Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.affiliation: Rottapharm Madaus, Via Valosa di Sopra 9, 20052 Monza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sabatini
authors.affiliation: Rottapharm Madaus, Via Valosa di Sopra 9, 20052 Monza, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lanza
authors.affiliation: Rottapharm Madaus, Via Valosa di Sopra 9, 20052 Monza, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Caselli
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Rienzo
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Menziani
authors.affiliation: Dipartimento di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Sbraccia
authors.affiliation: Dipartimento di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Molinari
authors.affiliation: Dipartimento di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Costa
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: andrea.cappelli@unisi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009287:Naphthyridines; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4
keywords: 5-HT4 receptor ligands; G-protein coupled receptor; Molecular modelling; Serotonin; Synthesis