Design of novel 5-HT(6) antagonists.

摘要

5-HT6 receptors are one of the recently discovered serotonin receptors. They are G-protein coupled receptors and are positively coupled to an adenylate cyclase second messenger system. When the present investigation began, biological functions of 5-HT6 receptors were poorly understood due to lack of selective agonists and antagonists. Pharmacological studies with the recently discovered selective 5-HT6 antagonists suggested that these receptors might play an important role in memory and cognitive disorders, eating disorders, anxiety and other neuropsychiatric disorders. However, there is contradicting evidence regarding the therapeutic usefulness of 5-HT6 antagonists, and additional studies need to be done with other structural classes of 5-HT6 antagonists. Roche antagonists were reported as first selective 5-HT6 antagonists, and we had earlier reported benzenesulfonyltryptamines as selective 5-HT 6 antagonists. There are several structural similarities in these two classes of compounds. Structural requirements of benzenesulfonyltryptamines were partly known when the present investigation began. The present investigation focused to: (i) further identify structural requirements of the benzenesulfonyltryptamines for binding at 5-HT6 receptors, (ii) determine if benzenesulfonyltryptamines bind in a similar fashion as the Roche antagonists, (iii) understand the similarities and dissimilarities in the mode of binding of tryptamine-based agonists and antagonists, (iv) analyze 3D-quantitative structure activity relationships, (v) build 5-HT6 receptor models using rhodopsin crystal structure as a template. The present investigation further extended the SAFIR of benzenesulfonyltryptamines, and suggested that benzenesulfonyltryptamines and Roche antagonists might be binding in a different manner. Receptor modeling and SAFIR studies indicated that the tryptamine-based agonists and antagonists might be binding in a different manner. During this process examples of two novel classes of 5-HT6 antagonists, and several novel 5-HT 6 ligands were developed. Members of two structural classes of antagonists were tested in drug discrimination studies which suggested that 5-HT 6 antagonists might be capable of modulating dopaminergic and/or cholinergic neurotransmission.