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

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 similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.

4-Phenyl quinoline derivatives as potential serotonin receptor ligands with antiproliferative activity.

Antagonists of signaling receptors are often effective non-toxic therapeutic agents. Over the years, there have been evidences describing the role of serotonin or 5-hydroxytryptamine (5-HT) in development of cancer. Although there are reports on the antiproliferative effects of some serotonin receptor antagonists, there are very few investigations related to understanding their structure-activity relationships. In this study, we report the screening of a library of 4-phenyl quinoline derivatives for their antiproliferative activities. Preliminary docking studies indicated that these ligands had the ability to bind to two of the serotonin receptors, 5-HT1B and 5-HT2B. The results of the in silico experiments were validated by performing in vitro studies on MCF-7 breast cancer cell line. The ethylpiperazine derivatives showed maximum toxicity against this cancer cell line. The compounds inhibited Calcium ion efflux (induced by serotonin) and ERK activation. One of the most active 4-phenyl quinoline derivatives (H3a) also induced apoptosis, thereby, suggesting the use of this scaffold as a potential anticancer drug.

Exhaustive CoMFA and CoMSIA analyses around different chemical entities: a ligand-based study exploring the affinity and selectivity profiles of 5-HT1A ligands.

The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands. [Formula: see text].

5-HT(1A) receptor: an old target as a new attractive tool in drug discovery from central nervous system to cancer.

The serotonin receptor subtype 5-HT(1A) was one of the first serotonin receptor subtypes pharmacologically characterized. This receptor subtype has long been object of intense research and is implicated in the pathogenesis and treatment of anxiety and depressive disorders. In recent years, new chemical entities targeting the 5-HT(1A) receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic uses in neuroprotection, cognitive impairment, Parkinson's disease, pain treatment, malignant carcinoid syndrome, and prostate cancer. This Perspective compares existing data on expression and signaling activity of the 5-HT(1A) receptor to a ligand with an intrinsic agonist or antagonist profile. Our purpose is also to make a complete overview, useful for underlining the features needed to select a specific pharmacological profile rather than another one. This aspect could be really interesting to consider and justify the 5-HT(1A) receptor as a new attractive target for drug discovery.