RESUMO
WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride) is an achiral phenylpiperazine derivative that binds with high affinity and selectivity to the 5-HT1A receptor. WAY-100635 displaced specific binding of the 5-HT1A radioligand, [3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), to rat hippocampal membranes with a pIC50 of 8.87. This represented a greater than 100-fold selectivity relative to binding at other 5-HT receptor subtypes and major neurotransmitter receptor, reuptake and ion channel sites. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HT1A receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concentrations, an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA2 value (at 0.3 nM) of 9.71. WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anaesthetised rat at doses which had no inhibitory action per se. In behavioural models, WAY-100635 itself induced no overt behavioural changes but potently antagonised the behavioural syndrome induced by 8-OH-DPAT in the rat and guinea-pig (minimum effective dose = 0.003 mg/kg s.c. and ID50 = 0.01 mg/kg s.c., respectively). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. These data indicate that WAY-100635 will be used as a standard antagonist in further studies of 5-HT1A receptor function.
Assuntos
Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/antagonistas & inibidores , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Temperatura Corporal/efeitos dos fármacos , Feminino , Cobaias , Hipotermia/induzido quimicamente , Íleo/efeitos dos fármacos , Íleo/fisiologia , Técnicas In Vitro , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Piperazinas/metabolismo , Piridinas/metabolismo , Ensaio Radioligante , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiologia , Ratos , Ratos Sprague-Dawley , Serotonina/fisiologia , Antagonistas da Serotonina/metabolismoRESUMO
The novel phenylpiperazine derivative, (+/-)-WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpro pionamide dihydrochloride), is a selective antagonist at both somatodendritic and postsynaptic 5-HT1A receptors. The IC50 of (+/-)-WAY100135 at the rat hippocampal 5-HT1A receptor was 34 nM, whereas its IC50 at a range of other receptor sites was > 2 microM. Up to a dose of 2.5 mg/kg i.v. (+/-)-WAY100135 induced a maximum 30% inhibition of raphe neuronal firing and (at 0.5 mg/kg i.v.) antagonised the inhibition of firing induced by 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) in anaesthetised rats. (+/-)-WAY100135 antagonised the action of 5-carboxamidoiodotryptamine in the guinea-pig ileum, with a pA2 of 7.2. (+/-)-WAY100135 had no agonist-like behavioural effects but antagonised the behavioural syndrome and hypothermia induced by 8-OH-DPAT in the rat and mouse, respectively. The interaction of (+/-)-WAY100135 with the 5-HT1A receptor was stereoselective; the (+)-enantiomer being markedly more active in binding, functional and behavioural studies. These data indicate that (+/-)-WAY100135 is the first highly selective antagonist at both somatodendritic and postsynaptic 5-HT1A receptors.
Assuntos
Piperazinas/farmacologia , Antagonistas da Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Eletrofisiologia , Feminino , Cobaias , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipotermia/induzido quimicamente , Hipotermia/tratamento farmacológico , Íleo/efeitos dos fármacos , Masculino , Camundongos , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Ensaio Radioligante , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Serotonina/análogos & derivados , Serotonina/farmacologia , EstereoisomerismoRESUMO
A series of N-(aminoiminomethyl)-1H-pyrrole-1-acetamides, related to guanfacine, were prepared and tested for antidiarrheal activity in castor oil dosed rats. trans-N-(Aminoiminomethyl)-2,5-dihydro-2,5-dimethyl-1H-pyrrole-1-acetami de (2), in which the dichlorophenyl ring of guanfacine is replaced by 2,5-dimethyl-2,5-dihydropyrrole, showed potent antidiarrheal activity but possessed only minimal cardiovascular activity in rats.