Two New βN-Alkanoyl-5-Hydroxytryptamides with Relevant Antinociceptive Activity

In this work, we describe a new route for the synthesis and the antinociceptive effects of two new βN-alkanoyl-5-hydroxytryptamides (named C20:0-5HT and C22:0-5HT). The antinociceptive activities were evaluated using well-known models of thermal-induced (reaction to a heated plate, the hot plate model) or chemical-induced (licking response to paw injection of formalin, capsaicin, or glutamate) nociception. The mechanism of action for C20:0-5HT and C22:0-5HT was evaluated using naloxone (opioid receptor antagonist, 1 mg/kg), atropine (muscarinic receptor antagonist, 1 mg/kg), AM251 (cannabinoid CB1 receptor antagonist, 1 mg/kg), or ondansetron (5-HT3 serotoninergic receptor antagonist, 0.5 mg/kg) 30 min prior to C20:0-5HT or C22:0-5HT. The substances both presented significant effects by reducing licking behavior induced by formalin, capsaicin, and glutamate and increasing the latency time in the hot plate model. Opioidergic, muscarinic, cannabinoid, and serotoninergic pathways seem to be involved in the antinociceptive activity since their antagonists reversed the observed effect. Opioid receptors are partially involved due to tolerant mice demonstrating less antinociception when treated with both compounds. Our data showed a quicker and simpler route for the synthesis of the new βN-alkanoyl-5-hydroxytryptamides. Both compounds demonstrated significant antinociceptive effects. These new compounds could be used as a scaffold for the synthesis of analogues with promising antinociceptive effects.

Serotoninergic Receptor Ligands Improve Tamoxifen Effectiveness on Breast Cancer Cells

Background: The tightly regulated pattern of serotonin (or 5-Hydroxytryptamine, 5-HT) in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis and angiogenesis. Antagonists of serotonin receptors or inhibitors of serotonin reuptake/synthesis may be co-prescribed with Tamoxifen in estrogen receptor-positive (ER+) tumors, and may modulate its efficacy. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT2A and 5-HT2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER+ cells. Methods: Cell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; CTGF mRNA levels have been measured by qPCR. All data were statistically analyzed using GraphPad Prism 7. Results: We found that SER were more effective on MCF7 ER+ cells (IC50 range 10.2µM - 99.2µM) compared to SKBR3 (IC50 range 43.3µM - 260µM) and MDA-MB231 BC cells (IC50 range 91.3µM - 306µM). Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 BC cells and modulated the expression of CTGF. Moreover, in a cell model of Tamoxifen-resistance, SER79 and SER68 restored drug responsiveness and reduced CTGF levels. Conclusions: These results identified new compounds potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.

5-HT2A serotoninergic receptor in the locus coeruleus participates in the first phase of lipopolysaccharide-induced fever

This study was aimed at testing the hypothesis that serotoninergic receptors in the locus coeruleus (LC) play a role in bacterial lipopolysaccharide-induced fever. To this end, 5-HT1A (WAY-100635; 3 μg/100 nL) and 5-HT2A (ketanserin; 2 μg/100 nL) antagonists were microinjected into the LC and body temperature was monitored by biotelemetry. Intra-LC microinjections of ketanserin or WAY-100635 caused no change in body temperature of euthermic animals. 5-HT2A antagonism abolished the first phase of the lipopolysaccharide-induced fever. Taken together, these results indicate that serotonin acting on 5-HT2A receptors in the LC mediates the first phase of the febrile response, whereas 5-HT1A receptors are not involved in the lipopolysaccharide-induced fever.