IHCH-2330 is a serotonergic drug related to compounds such as 2C-TFM and 25TFM-NBOMe. It acts as an agonist at the 5-HT2A and 5-HT2C receptors but is an antagonist at the 5-HT2B receptor, a profile which is hoped to eliminate the issues with cardiac valvulopathies associated with related compounds that act as agonists of 5-HT2B. While phenethylamine derivatives with an N-benzyl substitution such as 25TFM-NBOMe are able to bind to both 5-HT2A and 5-HT2B in an agonist-like conformation, IHCH-2330 was designed to exploit differences in the shape of the extended binding pocket adjacent to the active site which is occupied by 5-HT2 antagonist ligands such as risperidone. The pyridopyrimidinone group is able to occupy a side-extended pocket in 5-HT2A which retains an agonist-like bound conformation for the 4-trifluoromethyl group at the other end of the molecule, but in the 5-HT2B receptor the larger extended binding pocket causes the pyridopyrimidinone group to flip upward into the same position occupied by the pyridopyrimidinone group of risperidone, which pushes the receptor into an antagonist conformation. This builds upon earlier work using compounds such as Z3881312504 which exploits the same structural difference between the 5-HT2A and 5-HT2B receptors and shows a similar separation of 5-HT2A agonist from 5-HT2B antagonist activity, but with considerably lower potency.
See also IHCH-6122
References