Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter

Abstract

The serotonin transporter (SERT) is an integral membrane protein that exploits preexisting sodium-, chloride-, and potassium ion gradients to catalyze the thermodynamically unfavorable movement of synaptic serotonin into the presynaptic neuron. SERT has garnered significant clinical attention partly because it is the target of multiple psychoactive agents, including the antidepressant paroxetine (Paxil), the most potent selective serotonin reuptake inhibitor known. However, the binding site and orientation of paroxetine in SERT remain controversial. To provide molecular insight, we constructed SERT homology models based on the Drosophila melanogaster dopamine transporter and docked paroxetine to these models. We tested the predicted binding configurations with a combination of radioligand binding and flux assays on wild-type and mutant SERTs. Our data suggest that the orientation of paroxetine, specifically its fluorophenyl ring, in SERT’s substrate binding site directly depends on this pocket’s charge distribution, and thereby provide an avenue toward understanding and enhancing high-affinity antidepressant activity.

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

“…One of the thermostabilizing mutations, however, involves a residue (Thr439Ser) that is directly positioned within the central binding site, in close proximity to the bound SSRIs. Moreover, recent computational modeling of a wild-type SERT-paroxetine complex, in which the structure of the Drosophila DAT was used as a template for the SERT structure, yielded a pose for paroxetine in the SERT binding site that is different from that found in the SERT ts3 crystal structure 22 . In light of the computational study and because residue 439 is near the central binding site, we were motivated to determine crystal structures of SERT bound with SSRIs where residue 439 is the wild-type threonine amino acid.…”

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

“…One of the thermostabilizing mutations, however, involves a residue (Thr439Ser) that is directly positioned within the central binding site, in close proximity to the bound SSRIs. Moreover, recent computational modeling of a wild-type SERT-paroxetine complex, in which the structure of the Drosophila DAT was used as a template for the SERT structure, yielded a pose for paroxetine in the SERT binding site that is different from that found in the SERT ts3 crystal structure 21 . In light of the computational study and because residue 439 is near the central binding site, we were motivated to determine crystal structures of SERT bound with SSRIs where residue 439 is the wild-type threonine amino acid.…”

“…It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/204859 doi: bioRxiv preprint first posted online Oct. 17, 2017; page 4 of 15 structure, yielded a pose for paroxetine in the SERT binding site that is different from that found in the SERT ts3 crystal structure 21 . In light of the computational study and because residue 439 is near the central binding site, we were motivated to determine crystal structures of SERT bound with SSRIs where residue 439 is the wild-type threonine amino acid.…”

Transition‐Metal‐Free Multiple Functionalization of Piperidines to 4‐Substituted and 3,4‐Disubstituted 2‐Piperidinones

“…2) rather than to employ dehydrogenation of amides or the conventional ring‐closing metathesis of homoallyl amides . Thus, the success of this novel approach would provide, not only a new way for the remote mono and double functionalization of piperidines, but also the shortest route to pharmaceutical alkaloids such as Vesamicol, Paroxetine, Femoxetine, and Roche‐1 under an economical and ecofriendly fashion (Scheme , eq. 3).…”