Identification of a novel off-target of paroxetine: Possible role in sexual dysfunction induced by this SSRI antidepress

[Twentyoneguns]

https://www.sciencedirect.com/science/a ... d=coauthor


Latest from Melcangi

[Twentyoneguns]

Latest from Prof. R.C. Melcangi


This multidisciplinary work by the research unit coordinated by Prof. R.C. Melcangi of the University of Milan on SSRIs has been published in the Journal of Molecular Structure. Shareable link with free access and download to the full text until Sept. 2: https://authors.elsevier.com/c/1fQ7v_WRZ2kK1).



How was it possible to find a new off-target of paroxetine for the first time in a full 30 years after its commercialization?



A multidisciplinary approach was used. The first step involved an innovative computational method, developed by an Italian researcher in Milan, that can search the entire human structural proteome (tens of thousands of proteins) for potential binding sites of the drug under study, in this case paroxetine.



Importantly, this in silico screening was not intended to find targets in common with finasteride, but all proteins (off-target, i.e., other than the serotonin transporter) that could bind to paroxetine for purely structural reasons.



Among the potential binding sites returned by the software, among the most likely ones (based on their three-dimensional structure) was found to be phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to adrenaline (the last step in catecholamine biosynthesis), which is involved in several biological processes, including erection.



At this point, of course, the thing that struck the researchers was that the same off-target had previously been found (by the same researchers: Giatti, Silvia, et al. "Three-dimensional proteome-wide scale screening for the 5-alpha reductase inhibitor finasteride: identification of a novel off-target." Journal of medicinal chemistry 64.8 (2021): 4553-4566) for finasteride, a drug associated with sexual dysfunction, both during, and after discontinuation of the drug, (as the package inserts now report). So it was decided to investigate further and test whether indeed paroxetine also interacts with the PNMT enzyme, as the computational agnostic screening had suggested.



Further in silico analysis, in this case docking and molecular dynamics, indeed confirmed the result of the computational screening, in the sense that the drug-protein interaction indeed seemed to be able to take place without problems, moreover at the same catalytic site where norepinephrine is positioned to be methylated and form adrenaline. This suggests competitive inhibition.



After that, experimental assays were performed, first in vitro, and then in vivo: the in vitro assay actually found a partial inhibition of the PNMT enzyme, while the in vivo assay measured a reduced level of adrenaline (the product of PNMT, precisely) in the adrenal gland.



Both in vitro and in vivo experiments thus confirmed and validated the result of the computational screening, namely, a partial inhibition of the PNMT enzyme by paroxetine.



Since adrenaline intervenes in the mechanism of erection, antagonizing noradrenaline, these results suggest that paroxetine-induced sexual dysfunction may be due, at least in part, to PNMT inhibition. It should also be kept in mind that not everyone has the same expression levels of the enzyme, so for some, even partial inhibition of it could have very serious effects.



Further studies are needed to confirm that this inhibition is indeed a cause or concomitant cause of erectile dysfunction and to explore other potential mechanisms by which SSRI antidepressants might induce sexual side effects, both while taking the drug and after its discontinuation.



It is not discussed in the paper, but this inhibition could also help explain other effects (emotional, cognitive, ...?) of paroxetine, since adrenaline intervenes in various biological processes.



This finding is important not only because it finds a new unexpected off-target never before found that could explain sexual dysfunction, but also because it confirms that there are mechanisms in common between SSRIs and finasteride, as researchers had previously hypothesized, since finasteride and paroxetine share a same enzyme target (PNMT). This is an unexpected element that brings PSSD closer to PFS.



"It is interesting to note that different molecules (i.e., paroxetine and finasteride), with different chemical structures (i.e., a lipophilic base amine and an azasteroid), but producing a similar end-point phenotype (e.g., sexual dysfunction), are supposed to interact with the same enzymatic target, such as PNMT."



To cite the paper:

Giatti, Silvia, et al. "Identification of a novel off-target of paroxetine: Possible role in sexual dysfunction induced by this SSRI antidepressant drug." Journal of Molecular Structure 1268 (2022): 133690



More study from the University of Milan:



“Results obtained reveal that paroxetine significantly affects steroid levels, only in the colon but not in plasma. In particular, steroid modifications observed immediately after treatment are not overlap with those detected at withdrawal. Additionally, paroxetine treatment and its withdrawal impact gut microbiota populations differently. Altogether, these results suggest a biphasic effect of the drug treatment in the gut both on steroidogenesis and microbiota.”



Source:

Diviccaro, Silvia, et al. "Paroxetine effects in adult male rat colon: Focus on gut steroidogenesis and microbiota." Psychoneuroendocrinology (2022): 105828. https://doi.org/10.1016/j.psyneuen.2022.105828



Donations to University of Milan: https://www.gofundme.com/f/27l8qmes5c



In other news:

(scientific paper, PSSD) Yacov Reisman, Tommaso B. Jannini, Emmanuele A. Jannini. Post-Selective Serotonin Reuptake Inhibitor Sexual Dysfunctions (PSSD): Clinical Experience with a Multimodal Approach. J. Mens. Health 2022, 18(8), 165. https://doi.org/10.31083/j.jomh1808165

(scientific paper, depression) Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01661-0

(scientific paper, PSSD) Achour, V., M. Masson, C. Lancon, L. Boyer, and G. Fond. 2022. “Screening and Treatment of Post-Selective Serotonin Reuptake Inhibitors Sexual Dysfunctions.” L’Encephale, August. https://doi.org/10.1016/j.encep.2022.07.001.

(media, PSSD) For Some People, the Sexual Side Effects of SSRIs Never Go Away



Our website: postssrisyndrome.org

[flexstar13]

Why does nobody seems to care about this paper? In my opinion it is the first time you can make a lonk between pssd and pfs.

[thepineapple]

Why does nobody seems to care about this paper? In my opinion it is the first time you can make a lonk between pssd and pfs.

what can be done?