title: Optimization of the pharmacophore model for 5-HT7R antagonism. Design and synthesis of new naphtholactam and naphthosultam derivatives.
abstract: We present in this study an optimization of a preliminary pharmacophore model for 5-HT(7)R antagonism, with the incorporation of recently reported ligands and using an efficient procedure with the CATALYST program. The model consists of five features: a positive ionizable atom (PI), a H-bonding acceptor group (HBA), and three hydrophobic regions (HYD). This model has been supported by the design, synthesis, and biological evaluation of new naphtholactam and naphthosultam derivatives of general structure I (39-72). A systematic structure-affinity relationship (SAFIR) study on these analogues has allowed us to confirm that the model incorporates the essential structural features for 5-HT(7)R antagonism. In addition, computational simulation of the complex between compound 56 and a rhodopsin-based 3D model of the 5-HT(7)R transmembrane domain has permitted us to define the molecular details of the ligand-receptor interaction and gives additional support to the proposed pharmacophore model for 5-HT(7)R antagonism: (i) the HBA feature of the pharmacophore model binds Ser(5.42) and Thr(5.43), (ii) the HYD1 feature interacts with Phe(6.52), (iii) the PI feature forms an ionic interaction with Asp(3.32), and (iv) the HYD3 (AR) feature interacts with a set of aromatic residues (Phe(3.28), Tyr(7.43)). These results provide the tools for the design and synthesis of new ligands with predetermined affinities and pharmacological properties.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, and Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, E-28040 Madrid, Spain. mluzlr@quim.ucm.es
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: Esther
authors.initials: E
authors.lastname: Porras
authors.forename: M José
authors.initials: MJ
authors.lastname: Morcillo
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Soto
authors.forename: José L
authors.initials: JL
authors.lastname: Lavandera
authors.forename: José A
authors.initials: JA
authors.lastname: Ramos
authors.forename: Mireia
authors.initials: M
authors.lastname: Olivella
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D003198:Computer Simulation; D015195:Drug Design; D007031:Hypothalamus / Q000378:metabolism; D066298:In Vitro Techniques; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007769:Lactams; D008024:Ligands; D009281:Naphthalenes; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013844:Thiazoles; C104425:serotonin 7 receptor; C031721:naphthalene