Synthesis, Antidepressant Evaluation and Docking Studies of Long‐Chain Alkylnitroquipazines as Serotonin Transporter Inhibitors

Silva-Matus

et al. 2016

Archiv der Pharmazie

A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT R (K = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (K = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug-target interactions, which allowed rationalizing the observed affinities.

Section: Resultsmentioning

confidence: 99%

Synthesis and Docking of Novel 3‐Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5‐HT_1AR/SERT

Silva-Matus

et al. 2016

Archiv der Pharmazie

“…In this way, this study shows for the first time a selenium compound binding affinity with serotonin transporters and the serotonin receptors: 5HT 1a, 5HT 2a and 5HT 3 which might be useful to unravel the mechanism of action antidepressant-like effect exerted by several selenium compounds, as cited previously . Moreover, similar studies already demonstrated the antidepressant-like effect using this docking methodology in mice submitted to FST [ 69 – 71 ].…”

Section: Resultsmentioning

confidence: 76%

Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice

et al. 2017

A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist), ketanserin (a 5HT2a/c antagonist) and ondansetron (a selective 5ht3 antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D1 antagonist) and sulpiride (D2 antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.

“…New SERT inhibitors, compounds KW117 ( 6 ), AZ05 ( 7 ), AZ07 ( 8 ), AB5A ( 9 ), AB9 ( 10 ), AB21 ( 11 ) and AB22 ( 12 ), possessed a nanomolar affinity for SERT ( Table 1 ). Compounds KW117 ( 6 ), AZ05 ( 7 ) and AZ07 ( 8 ) exhibited moderate antidepressant activity in the in vivo Porsolt forced swim test [ 6 ]. It appeared that almost all of the examined compounds (besides 5-HT 1A receptor agonist 8-OH-DPAT, SSRI fluvoxamine against SH-SY5Y and AB9 against both tumor lines) exhibited moderate to high cytotoxic activity at the micromolar level against neuroblastoma and prostate cancer cells ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…KW117 (6-nitro-2-(4-octylpiperazin-1-yl)quinoline hydrochloride) ( 6 ), AZ05 (6-nitro-2-(4-nonylpiperazin-1-yl)quinolone hydrochloride) ( 7 ), and AZ07 (6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride) ( 8 ) were obtained as described in Gabrielsen et al [ 6 ]. New compounds: AB5A (2-[4-(4-fluorobenzyl)piperazin-1-yl]-6-nitroquinoline hydrochloride) ( 9 ), AB9 (6-nitro-2-[4-(2-phenylethyl)-piperazin-1-yl]-6-nitroquinoline hydrochloride) ( 10 ), AB21 (2-[4-(cyclohexylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride) ( 11 ), and AB22 (2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride) ( 12 ) were synthesized as described below in Section 6 —Experimental procedures.…”

Section: Methodsmentioning

confidence: 99%

“…In this paper, we examined the cytotoxic activity of several compounds endowed with serotonergic activity including known compounds—fluoxetine ( 1 ), paroxetine ( 2 ), fluvoxamine ( 4 ) (and acetylated derivatives of paroxetine ( 3 ) and fluvoxamine ( 5 )) ( Figure 1 ), compounds ( 6 – 8 ) from our previous studies [ 6 ] and new synthesized compounds ( 9 – 12 ) as serotonin transporter (SERT) inhibitors ( Table 1 ) as well as 5-HT 1A receptor agonists (2 R )-(+)-8-Hydroxy-2-(di- n -propylamino)tetralin hydrobromide (8-OH-DPAT) ( 13 ), 4-Fluoro- N -[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S 14506) ( 14 ) and antagonist N -[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]- N -2-pyridinylcyclohexanecarboxamide maleate (WAY100635) ( 15 ) ( Figure 2 ). The antiproliferative activity of the compounds was examined in SH-SY5Y and PC-3 cancer cell lines (with Balb/c 3T3 cells as a reference).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oncotoxic Properties of Serotonin Transporter Inhibitors and 5-HT1A Receptor Ligands

Walory

Mielczarek

Jarończyk

et al. 2018

IJMS

Self Cite

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with...