Synthesis And Modification Of BZD And THIQs Non-competitive AMPA Acceptor Antagonists

Depression is one of the most common neurological problems resulted from the disorder of Glutamatergic neurotransmission which is mediated by ionotropic receptors (iGluRs) and metabotropic receptors (mGluRs). The iGluRs are ligand gated ion channels which are further subdivided into three classes based on their affinity for specific agonists: the N-methyl-D-aspartic acid (NMDA), the kainic acid (KA), andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtpypes. NMDA receptor antagonists are the first one being applied for the antidepression therapy, while because of being considered relation with some irreversible damage, they are now replaced by AMPA receptor antagonists, which are found with more active neuromodulating effects and less adverse effects. 2, 3-Benzodiazepine (2, 3-BZD) and tetra- hydroisoquinolines (THIQs) are two representative AMPAR antagonists, and they have received considerable attention due to their diverse activity to neuromodulating effects. This paper focuses on 2, 3-BZDs and THIQs giving following discussion:1. The Friedel-Crafts acylation is chosen as the key step during sythesis of BZD derivatives. The synthetic method is considered by trying a series of reaction conditions including screening acylating reagent, catalyst, solvent, reaction temperature and equivalent of the substrates. The key intermediate 1-[2-(4-Bromo-benzoyl)-4, 5-dimethoxy-phenyl]–propan-2-one K-3 which is prepared by applying the optimized condition, then is dehydrated with hydrazine hydrate in the presence of concentrated sulfuric acid to give 1-(4-Bromo-phenyl)-7, 8- dimethoxy-4-methyl-5H-benzodiazepine K-Br-BZD.2. The modification of BZD is proceeded by applying the palladium catalyzed amide coupling reaction and provide two BZD derivatives: 7, 8–dimethoxy-1-(4-methoxy-phenyl)-4-methyl-5H-benzodiazepine K- 347 and 7, 8-dimethoxy-1-(4-nitro-phenyl)-4-methyl-5H-benzo- diazepine K-353.3. Different R1-4 and R7 substituted phenyl acetones are prepared from benzaldehyde and phenyl cyanide; different hydrazine are prepared from different acid esters; different hydrazones was prepared from the obtained phenyl acetones and hydrazines then undergoing reductive reaction to provide the key intermediate hydrazide, which via Pictet-Spengler reaction give 65 new THIQs.4. The configuration of the trans and cis isomers are confirmed by analysis of the X-ray of A-2 and the coupling constant 3JHH of B-13.5. Detailed discussion about the effects resulted from R1-4, R5, R6, R7 on the configuration of the THIQs are involved in the paper. R1-4 effect on both coupling reaction and configuration of the products. R6, R7 have distinct effects on the steteoselectivity. R5 does not show clear effects on the products configuration, while when R5 is p-tosyl group, it appears highly stereoselective character.6. The structure of the desired BZD derivatives and THIQ derivatives are comparable to the 4-feature pharmacophore model, and they could be valuable for following bioactivity test on antidepression or anticonvulsant.