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1.
Bioorg Med Chem ; 16(6): 3309-20, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18083579

RESUMEN

To identify potent and selective 5-HT(2C) receptor agonists, a series of novel benzazepine derivatives were synthesized, and their structure-activity relationships examined. The compounds were evaluated for their 5-HT(2C), 5-HT(2A), and 5-HT(2B) receptor binding affinity and intrinsic activity for the 5-HT(2C) and 5-HT(2A) receptors. Among these compounds, 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine (6) was effective in a rat penile erection model when administered po, which is a symptom of the serotonin syndrome reflecting 5-HT(2C) receptor activation. Moreover, compound 6 was characterized as a partial agonist of 5-HT(2A) receptors; therefore, it had little effect on the cardiovascular system.


Asunto(s)
Benzazepinas/química , Benzazepinas/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Animales , Benzazepinas/síntesis química , Sistema Cardiovascular/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Ratas , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2B/efectos de los fármacos , Relación Estructura-Actividad
2.
Bioorg Med Chem ; 16(4): 1966-82, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18035544

RESUMEN

A series of novel indazole derivatives were synthesized, and their structure-activity relationships examined in order to identify potent and selective 5-HT2C receptor agonists. Among these compounds, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348) had a good in vitro profile, that is, high agonistic activity to the human 5-HT2C receptor subtype (EC50 = 1.0 nM) and high selectivity over 5-HT2A receptors. This compound was also effective in a rat penile erection model when administered p.o.


Asunto(s)
Indazoles/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/síntesis química , Animales , Etilaminas/síntesis química , Etilaminas/farmacología , Humanos , Indazoles/síntesis química , Erección Peniana/efectos de los fármacos , Ratas , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad
3.
Eur J Pharmacol ; 483(1): 37-43, 2004 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-14709324

RESUMEN

YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, showed a high affinity for cloned human 5-HT(2C) receptors (K(i): 0.89 nM). The functional selectivity for 5-HT(2C) receptors in the 5-HT(2) receptor family was the highest among 5-HT(2C) receptor agonists, including m-chlorophenylpiperazine (mCPP) and Ro60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine). Oral administration of YM348 induced penile erections and hypolocomotion in rats, being completely inhibited by a selective 5-HT(2C) receptor antagonist, SB242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline). The dose-response curve for penile erections, unlike that for hypolocomotion, was an inverted U-shape in the dose range of 0.0677-2.03 mg/kg. A selective 5-HT(2A) receptor antagonist, MDL100907 (R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol), and a selective 5-HT(2B) receptor antagonist, RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine), had no effect on the decline in penile erection frequency at 2.03 mg/kg of YM348. YM348 did not affect blood pressure at 2.03 mg/kg. In conclusion, YM348 is a novel, potent and orally active 5-HT(2C) receptor agonist, and neither the activation of 5-HT(2A) or 5-HT(2B) receptors nor a cardiovascular effect is likely to contribute to the inverted U-shape dose-response curve for penile erections.


Asunto(s)
Indazoles/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/farmacología , Aminopiridinas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Células CHO , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Clonación Molecular , Cricetinae , Depresión Química , Relación Dosis-Respuesta a Droga , Hemodinámica/efectos de los fármacos , Indoles/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Fosfatidilinositoles/metabolismo , Pirimidinas/farmacología , Ratas , Transmisión Sináptica/efectos de los fármacos
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