Optimization of the Pharmacophore Model for 5-HT <inf>7</inf> R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives

María L. López-Rodríguez, Esther Porras, M. José Morcillo, Bellinda Benhamú, Luis J. Soto, José L. Lavandera, José A. Ramos, Mireia Olivella, Mercedes Campillo, Leonardo Pardo

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71 Citations (Scopus)

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 (111) 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.
Original languageEnglish
Pages (from-to)5638-5650
JournalJournal of Medicinal Chemistry
Volume46
DOIs
Publication statusPublished - 18 Dec 2003

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