Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands |
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Authors: | Holenz Jörg Mercè Ramon Díaz José Luis Guitart Xavier Codony Xavier Dordal Alberto Romero Gonzalo Torrens Antoni Mas Josep Andaluz Blas Hernández Susana Monroy Xavier Sánchez Elisabeth Hernández Enrique Pérez Raquel Cubí Roger Sanfeliu Olga Buschmann Helmut |
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Affiliation: | Department of Medicinal Chemistry, Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain. jholenz@esteve.es |
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Abstract: | Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity. |
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