5-HT1A receptor agonists(Serotonin 1a (5-HT1a) receptor agonists), 5-HT2C receptor agonists(Serotonin 2c (5-HT2c) receptor agonists), D2 receptor antagonists(Dopamine D2 receptor antagonists)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Anxiety Disorders

Originator Organization

Les Laboratoires Servier SAS

Active Organization-

Inactive Organization

Les Laboratoires Servier SAS

Drug Highest PhaseDiscontinuedPreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC24H27ClFN3O2

InChIKeyHWLZKPKZVOLFGK-UHFFFAOYSA-N

CAS Registry286369-38-8

View All Structures (2)

100 Clinical Results associated with S-14506

100 Translational Medicine associated with S-14506

100 Patents (Medical) associated with S-14506

Literatures (Medical) associated with S-14506

01 Aug 2013·ToxicologyQ3 · MEDICINE

The effects of 8-OH-DPAT on neuroinflammation after sarin exposure in mice

Q3 · MEDICINE

Article

Author: Teresa L. Garrett ; James B. Lucot ; Kaushal Joshi ; John J. Schlager ; David R. Cool ; Molly Chapleau ; Christine M. Rapp

Poisoning by organophosphate nerve agents can induce seizures which rapidly become refractory to treatment and result in brain damage. Current therapies have only a narrow time frame for effective administration after poisoning. 5-HT1A agonists were tested for efficacy in mice against a seizure-producing combination of the carboxylesterase inhibitor 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP) and sarin, producing an LD20-40. Administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased glial fibrillary acidic protein (GFAP) staining in mice when administered 1min after CBDP and sarin while other 5-HT1A agonists buspirone and S-14506 were not effective. The reduction in GFAP staining by 8-OH-DPAT remained significant when a single dose was administered 2h after the toxic challenge. In addition, 8-OH-DPAT reversed the increase in the inflammatory factor IL-1β in the dentate gyrus and amygdala but did not reduce positive TUNEL staining in the dentate gyrus. Due to the failure of the two other agonists to provide protection, the 5-HT1A antagonist WAY-100635 was tested. WAY-100635 was found to neither reverse the neuroprotective effects of 8-OH-DPAT nor worsen the damage when given alone, making a role for this receptor unlikely. The neuroprotective effects of 8-OH-DPAT appear to lie within its secondary pharmacology.

01 Jan 2010·Current Radiopharmaceuticalse

Evaluation of [11C]S14506 and [18F]S14506 in Rat and Monkey as Agonist PET Radioligands for Brain 5-HT1A Receptors

Article

Author: Pike, Victor W. ; Innis, Robert B. ; Zoghbi, Sami S. ; Liow, Jeih-San ; Hong, Jinsoo ; Lu, Shuiyu

In vitro and ex vivo measurements have shown that the binding of the selective high-affinity agonist, S14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxy-naphthyl)piperazine), to 5-HT(1A) receptors, is similar in affinity (K(d) = 0.79 nM) and extent (B(max)) to that of the antagonist, WAY 100635. We aimed to test whether S14506, labeled with a positron-emitter, might serve as a radioligand for imaging brain 5-HT(1A) receptors in vivo with positron emission tomography (PET). Here we evaluated [(11)C]S14506 and [(18)F]S14506 in rat and rhesus monkey in vivo. After intravenous administration of [(11)C]S14506 into rat, radioactivity entered brain, reaching 210% SUV at 2 min. Radioactivity uptake into brain was higher (~ 350% SUV) in rats pre-treated with the P-glycoprotein (P-gp) inhibitor, cyclosporin A. In rhesus monkey, peak brain uptake of radioactivity after administration of [(11)C]S14506 or [(18)F]S14506 was also moderate and for [(11)C]S14506 increased from ~ 170% SUV after 7 min, to 240% SUV in a monkey pre-treated with the P-gp inhibitor, tariquidar. The ratios of radioactivity in 5-HT(1A) receptor-rich regions, such as cingulate or hippocampus to that in receptor-poor cerebellum reached between 1.35 and 1.5 at 60 min for both [(11)C]S14506 and [(18)F]S14506. [(11)C]S14506 gave one major polar radiometabolite in monkey plasma, and [(18)F]S14506 gave three and two more polar radiometabolites in rat and monkey plasma, respectively. The rat radiometabolites of [(18)F]S14506 did not accumulate in brain. [(18)F]S14506 was not radiodefluorinated in monkey. Thus, despite high-affinity and lack of troublesome brain radiometabolites, both [(11)C]S14506 and [(18)F]S14506 were ineffective for imaging rat or monkey brain 5-HT(1A) receptors in vivo, even under P-gp inhibited conditions. Explanations for the failure of these radioligands are offered.

01 Oct 2009·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Mutant 5-Hydroxytryptamine_1AReceptor D116A Is a Receptor Activated Solely by Synthetic Ligands with a Rich Pharmacology

Q3 · MEDICINE

Article

Author: Palmier, Christiane ; Bernois, Sophie ; Tardif, Stephanie ; Cussac, Didier ; Heusler, Peter ; De Vries, Luc ; Leger, Celine ; Finana, Frederic

Like other biogenic amine G protein-coupled receptors, mutation of the conserved aspartatic residue into alanine at position 116 (D116A(3.32)) in the 5-hydroxytryptamine (5-HT)(1A) receptor greatly affects 5-HT binding and signal transduction. [(3)H]8-Hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and [(3)H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100,635) are capable to bind the 5-HT(1A)-D116A mutant and, using these radioligands, we show here that this mutation dramatically reduces the affinities of the selective 5-HT(1A) agonists N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-methylamino methyl]piperidine (F13640), 3-chloro-4-fluorophenyl-(4-fluorophenyl-4-{[(5-methyl-6 methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone (F13714), and 2-[5-[3-(4-methylsulfonylamino)benzyl-1,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694247) and that of 5-carboxamidotryptamine. Although to a lesser extent, the binding of buspirone, (+)-flesinoxan, (-)-pindolol, and (-)-8-OH-DPAT are also highly decreased. In contrast, affinities of the 5-HT(1A) ligands WAY100,635, spiperone, (-)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz {c,d}indole-6-carboxamide (LY228,729), and 1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl) piperazine (S14506) and the prototypical 5-HT(1A) agonist (+)-8-OH-DPAT are only slightly affected by the mutation, suggesting a moderate contribution of Asp116 to the binding pocket for these latter. Furthermore, LY228,729, S14506, and (+)-8-OH-DPAT induce a potent and efficacious coupling of the 5-HT(1A)-D116A receptor to G protein activation as measured by Ca(2+) mobilization and guanosine 5'-O-(3-[(35)S]thio)triphosphate binding in Chinese hamster ovary cells as well as by G protein-coupled inwardly rectifying potassium channel current activation in Xenopus laevis oocytes. It is interesting that the selective 5-HT(1A) antagonist WAY100,635 shows potent partial agonist activity at the 5-HT(1A)-D116A mutant, whereas spiperone maintains its inverse agonist properties. The pharmacological approach reported here re-evaluates the binding and functional properties of the 5-HT(1A)-D116A receptor and describes for the first time this mutant as a receptor activated solely by synthetic ligands (RASSL), with a rich pharmacology. By bioengineering animal models incorporating this RASSL, one may further explore the role of 5-HT(1A) receptor signaling in the central nervous system as well as G(i) protein-mediated signaling pathways in other tissues.

100 Deals associated with S-14506

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Preclinical	-	Les Laboratoires Servier SAS	-

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