Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands

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.