Medicinal Chemistry Driven Approaches Toward Novel and Selective Serotonin 5-HT6 Receptor Ligands

• Published in: Journal of medicinal chemistry Vol. 48; no. 6; pp. 1781 - 1795
• Main 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
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 24-03-2005
• Subjects: Adenylyl Cyclases - biosynthesis; Benzoxazines - chemical synthesis; Benzoxazines - chemistry; Biological and medical sciences; Cell Line; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Radioligand Assay; Receptors, Serotonin - drug effects; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Agonist; Nitrogen heterocycle; 5-HT6 serotonin receptor; Selectivity; Organic carbamate; In vitro; Sulfur heterocycle; Structure activity relation; Piperidine derivatives; Bicyclic compound; Affinity; Aromatic compound; Antagonist; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049615n

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-HT6 receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT6 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-HT6 agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT6 receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.