SAR studies on new bis-aryls 5-HT 7 ligands: Synthesis and molecular modeling Eduard Badarau a,b , Ryszard Bugno c , Franck Suzenet a, * , Andrzej J. Bojarski c, * , Adriana-Luminita Finaru b , Gérald Guillaumet a a Institut de Chimie Organique et Analytique, Université d’Orléans, UMR-CNRS 6005, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France b Centrul de Cercetare ‘Chimie Aplicata ˘s ßi Inginerie de Proces’, Universitatea din Baca ˘u, Calea Ma ˘ra ˘s ßesti, nr. 157, 600115 Baca ˘u, Romania c Institute of Pharmacology, Polish Academy of Sciences, Sme ˛tna 12, Kraków 31-343, Poland article info Article history: Received 21 September 2009 Revised 13 January 2010 Accepted 14 January 2010 Available online 18 January 2010 Keywords: 5-HT 7 receptors Bis-aryls SAR Molecular modeling abstract Structure–activity relationships of a series of bis-arylic compounds, investigated as 5-HT 7 R ligands, are reported. The main structural modifications involved a central aryl moiety (phenyl, pyridine, diazine, tri- azine) and the nature and position of an amine-containing aliphatic chain. The affinity of the synthesized compounds (26 nM–10 lM) was systematically correlated with other previously reported series of bis- arylic ligands and rationalized by a ligand-based pharmacophore approach. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Due to serotonin’s multiple implications in many physiological processes in both the CNS and at periphery, 1 the discovery of po- tent and selective serotoninergic ligands keeps motivating the sci- entific community. Since the crystal structure of its receptors is still unresolved, many of the newly discovered serotoninergic hits were identified via a high-throughput screening (HTS) approach. Subsequently, these hits were improved in terms of their biological properties by various structural modifications. Identification of the essential chemical features of ligands, indispensable to their bio- logical activity seems of crucial importance, as it allows a rational design of future derivatives. One of the most straightforward methods consists in conducting different simplifications on more complex, biologically active, chemical structures. In the case of 5- HT 7 receptors, such simplifications led Rault and co-workers to dis- cover the bis-aryl compound 3 (Fig. 1). 2 Using the same approach, we are presenting the design, synthesis and SAR studies of new bis- aryl 5-HT 7 receptor ligands. One of the several methods for rationalizing SAR data, which has proven its efficacy in the case of transmembrane receptors, is the pharmacophore-based approach. This method helps to better understand ligand-protein interactions through the discovery of a common binding pattern (a pharmacophore model) of particular classes of ligands. In the case of 5-HT 7 Rs, several pharmacophore models have been published, 3–8 and they are characterized by the presence of at least four pharmacophore features: a positive ion (PI, a basic nitrogen proven to interact with an Asp residue in the binding site), a hydrogen-bond acceptor (HBA, usually an oxygen or an aromatic nitrogen) and two hydrophobic regions (HYD, aro- matic or aliphatic, specific to each reported model). Beside the PI fea- ture (mandatory for all the monoamine-type neurotransmitters or ligands), it has to be stressed that all the previously 5-HT 7 validated models also included an HBA feature. However, a significant number of potent ligands do not have hydrogen-bond acceptor groups. Thus, 0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2010.01.035 * Corresponding authors. E-mail addresses: franck.suzenet@univ-orleans.fr (F. Suzenet), bojarski@if- pan.krakow.pl (A.J. Bojarski). N O O N O O N O O simplification 1 simplification 2 2 1 3 Figure 1. Rational simplifications of aporphine-based ligand 1 leading to discovery of bis-arylic ligand 3. Bioorganic & Medicinal Chemistry 18 (2010) 1958–1967 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc