Novel multi target-directed ligands targeting 5-HT4 receptors with in cellulo antioxidant properties as promising leads in Alzheimer's disease

Abstract

Highlights • Conception and synthesis of new MTDLs combining 5-HT4R agonist activity and antioxidant properties • All compounds showed good %inhibition at 10-6M on 5-HT4R, with 9b and 9g showing Ki < 15 nM on 5-HT4R as well as agonist profile. • In vitro and in cellulo antioxidant effects were evaluated • 9b is the best compromise regarding the 5-HT4R activity and antioxidant properties

Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents

“…The multistep synthesis started with the activation of 4-amino-5-chloro-2-methoxybenzoic acid ( 1 ) with CDI, followed by the synthesis of β-keto ester ( 2 ) that was further engaged in reaction of nucleophilic substitution with N -Boc-4-(iodomethyl)piperidine ( 3 ), followed by reactions of saponification and decarboxylation to afford intermediate 4 [ 30 , 31 ]. After the reaction, the intermediate 4 of -Boc deprotection was alkylated with tert -butyl- N -(2-bromoethyl)carbamate to afford intermediate 5 [ 28 ]. After another reaction of -Boc deprotection, we performed a reaction of peptidic coupling with the carboxylic acid ( 6 ), after which was the last step of amidation of two esters in order to obtain final product 8 ( ENT-C199 ) in a 68% yield ( Scheme 1 ).…”

“…Indeed, in our previous work, we showed that by modifying the third position of LM22A-4, we can improve the TrkB activity [ 18 ]. Other studies have shown that a large variety of substitutions is allowed on the piperidine ring of RS67333 in order to obtain molecules that will possess an affinity towards the 5-HT 6 receptor [ 27 ], antioxidant [ 28 ], or AChE inhibition [ 29 ] properties, while preserving good affinity and an agonistic profile towards the 5-HT 4 receptor.…”

30th Annual GP2A Medicinal Chemistry Conference

“…Some preliminary works highlighted first compounds with this dual activity [ 180 ]. From a well-known 5-HT4R scaffold (aminochlorobenzophenone), we have connected different antioxidant scaffold.…”

Small Molecule Drugs for Treatment of Alzheimer’s Diseases Developed on the Basis of Mechanistic Understanding of the Serotonin Receptors 4 and 6

“…In 2019, Lanthier et al [48] generated a MTDL targeting both activation of the 5-HT4R while also bearing antioxidant activities; hereby being able to both control Ab protein accumulation and prevent toxicity of reactive oxygen species (ROS) in neuronal cells [48].…”

“…Compound 26 was developed by combining the 5-HT4R chloro-aniline pharmacophore (22) and structures (23)(24)(25) having antioxidant properties [48].…”