Synthesis and SAR study of Meperidine Analogues as Selective Serotonin Reuptake Inhibitors (SSRIs)

Meperidine has been shown to have potent binding affinity for serotonin transporters (SERT) (Ki = 41 nM) and be an inhibitor of serotonin reuptake. Based upon these pharmacological results meperidine has been identified as a lead compound for the development of a novel class of serotonin-selective reuptake inhibitors (SSRIs). A variety of potent analogues of meperidine have been synthesized and evaluated in vitro as potential ligands for the serotonin transporter. Substitutions have been made on the aryl ring, the ester moiety and the piperidine nitrogen of meperidine. Potent analogues of the aryl substituted series that included 4-iodophenyl, 2-naphthyl, 3,4-dichlorophenyl and 4-biphenyl meperidine derivatives were synthesized and chosen for further optimization of the benzyl ester analogues. Benzyl ester analogues included 4-nitro, 4-methoxyl and 3,4-dichloro benzyl analogues and exhibited high potency for serotonin transporters and high selectivity over the dopamine transporter (DAT) and the norepinephrine transporter (NET). Also the N-demethylated analogues improve the binding affinity and selectivity for serotonin transporter. The analogue 4- (carboxymethoxybenzyl)-4-(4-iodophenyl) piperidine (69f), was found the most potent (Ki=0.6 nM) and selective ligand for serotonin transporter (DAT/SERT >4500; NET/SERT >4500) for the series and has been advanced to in vivo evaluation.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Year

2010

Author dc:creator

• Gu, Xiaobo

Contributors dc:contributor

• Trudell, Mark L.
• Gibb, Bruce C.
• Wang, Guijun

• meperidine
• piperidine
• serotonin transporter
• SSRIs
• antidepressant

Repository record dc:identifier

https://scholarworks.uno.edu/td/1111

OAI identifier oai:identifier

oai:scholarworks.uno.edu:td-2092