Discovery of benzamide analogues as a novel class of 5-HT₃ receptor agonists.
A 5-HT₃ receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT₃A receptor yielded substantial information concerning the analogues as 5-HT₃ receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT₃ receptor agonist, as it does not possess a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT₃ receptors by binding to an allosteric site in the receptor complex.
Department of Medicinal Chemistry, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark. chj@farma.ku.dk
Charlotte G
CG
Jørgensen
Bente
B
Frølund
Jan
J
Kehler
Anders A
AA
Jensen
D000495:Allosteric Site; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001549:Benzamides; D008024:Ligands; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists