5-HT<sub>1A</sub> Receptor: An Old Target as a New Attractive Tool in Drug Discovery from Central Nervous System to Cancer

Fiorino, Ferdinando; Severino, Beatrice; Magli, Elisa; Ciano, Antonio; Caliendo, Giuseppe; Santagada, Vincenzo; Frecentese, Francesco; Perissutti, Elisa

doi:10.1021/jm400533t

Cited by 87 publications

(77 citation statements)

References 132 publications

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“…Moreover, 5-HT 1A receptor activation appears to increase prostate cell proliferation, via stimulation of the Akt/mitogen-activated protein kinase pathway (Hsiung et al, 2005;Dizeyi et al, 2011), and the 5-HT 1A receptor antagonist NAN190 reduces prostate cell proliferation (Dizeyi et al, 2004). Based on these data, 5-HT 1A receptors are considered as an attractive target for drug development in such context (Fiorino et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Nascimento-Viana

Carvalho

Nasciutti

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with a 1A -adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of a 1D -adrenoceptors and 5-hydroxytryptamine (serotonin) (5-HT) 1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N-phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on-or off-target receptors. LDTs' potency was estimated in intracellular Ca 21 elevation assays using cells overexpressing human a 1 -adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs' effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of a 1A -, a 1D -adrenoceptors, and 5-HT 1A receptors (K i values in the nanomolar range), and fully inhibited phenylephrine-and 5-HT-induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED 50 of 0.15 and 0.09 mg.kg 21 , respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment.

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Section: Introductionmentioning

confidence: 99%

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Nascimento-Viana

Carvalho

Nasciutti

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…This correlation is confirmed by the observation that significant antidepressant activity is elicited by 5-HT 1A R agonists [4]. Though the mechanism responsible for their antidepressant action is still unclear, desensitization or downregulation of presynaptic 5-HT 1A Rs appears to be implicated in this pharmacological effect.…”

Section: Depressionmentioning

confidence: 66%

“…Among the 5-HTRs, the 5-HT 1A subtype was the first to be cloned [3] and pharmacologically characterized, and it is one of the most studied. For this reason, it is often ironically called "old target" [4]. The human 5-HT 1A R consists of 422 amino acid residues with a molecular weight of about 46,000 Da.…”

Section: Serotonin -A Chemical Messenger Between All Types Of Living mentioning

confidence: 99%

“…As in the case of presynaptic receptors, the activation of postsynaptic 5-HT 1A Rs generally decreases the firing rate of postsynaptic cells. Electrophysiological, pharmacological, and biochemical evidences have demonstrated that 5-HT 1A Rs are localized in primary afferent neurons [4]. They are also present in the gut, in the enteric nervous system, as well as in smooth muscle, where their activation inhibits relaxation or contraction.…”

Section: -Ht 1amentioning

confidence: 99%

“…Rs have also been demonstrated to mediate an endogenous inhibitory control of nociception evoked by thermal noxious stimuli [4].…”

Section: -Ht 1amentioning

confidence: 99%

See 2 more Smart Citations

4WD to Travel Inside the 5-HT1A Receptor World

Quaglia¹,

Cifani²,

Bello³

et al. 2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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5-HT 1A receptor is one of the most important members of the numerous families of serotoninergic receptors. Though it was the first 5-HT receptor to be identified and cloned, the knowledge of its activation/transduction mechanisms, mediated effects, and connection with other systems is still uncompleted. For this reason, relevant is the study of the four Ws of the title: first of all "who" this receptor is, then "why" it continues to be a so attractive target after several years after its identification, then "where" is 5-HT 1A receptor expressed within the body, and, finally, "what" effects this receptor can elicit under physiological and pathological conditions. Obviously, more and more potent, safe, and selective "drugs" might be discovered once the responses to these questions are given.

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Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway

Wang

Zhu

et al. 2020

FEBS Open Bio

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Vortioxetine is a potent antagonist of the 5-hydroxytryptamine receptor and serotonin transporter and has been reported to function as an antidepressant in the treatment of major depressive disorder. However, its antitumor effects remain unclear. Here, we examined whether vortioxetine affects the characteristics of GC cells. Cell viability was measured by a colony formation assay and, in addition, cell invasion, migration and apoptosis assays were performed with a transwell assay and a flow cytometry assay. Protein levels were measured by western blotting. We found that vortioxetine inhibited the proliferation, invasion and migration abilities of AGS cells. Additionally, vortioxetine could induce apoptosis and autophagy by increasing the levels of Bax, active caspase-3/-9, Beclin-1 and light chain 3, as well as by downregulating Bcl-2 and P62. Further investigations indicated that vortioxetine regulated apoptosis and autophagy via activation of the phosphoinositide 3-kinase/AKT pathway. Taken together, our data suggest that vortioxetine has cytotoxic effects against GC AGS cells as a result of inhibiting proliferation, invasion and migration, as well as by inducing apoptosis and autophagy through the phosphoinositide 3-kinase/ AKT pathway.

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5-HT_1A Receptor: An Old Target as a New Attractive Tool in Drug Discovery from Central Nervous System to Cancer

Cited by 87 publications

References 132 publications

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

4WD to Travel Inside the 5-HT1A Receptor World

Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway

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5-HT1A Receptor: An Old Target as a New Attractive Tool in Drug Discovery from Central Nervous System to Cancer

Cited by 87 publications

References 132 publications

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

4WD to Travel Inside the 5-HT1A Receptor World

Vortioxetine induces apoptosis and autophagy of gastric cancer AGS cells via the PI3K/AKT pathway

Contact Info

Product

Resources

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5-HT_1A Receptor: An Old Target as a New Attractive Tool in Drug Discovery from Central Nervous System to Cancer