Asunto(s)
Antipsicóticos/metabolismo , Clozapina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas Adrenérgicos alfa/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Cricetinae , Células Eucariotas/efectos de los fármacos , Células Eucariotas/metabolismo , Humanos , Prazosina/metabolismo , Ensayo de Unión RadioliganteRESUMEN
Iloperidone (HP 873; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl]ethanone) is a compound currently in clinical trials for the treatment of schizophrenia. Iloperidone displays affinity for dopamine D2 receptors and for 5-HT2A receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic. Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes. We employed receptor binding assays using membranes from cells stably expressing human dopamine D1, D2S, D2L, D3, D4 and D5 and 5-HT2A and 5-HT2C receptors and rat 5-HT6 and 5-HT7 receptors. Iloperidone displayed higher affinity for the dopamine D3 receptor (Ki = 7.1 nM) than for the dopamine D4 receptor (Ki = 25 nM). Iloperidone displayed high affinity for the 5-HT6 and 5-HT7 receptors (Ki = 42.7 and 21.6 nM, respectively), and was found to have higher affinity for the 5-HT2A (Ki = 5.6 nM) than for the 5-HT2C receptor (Ki = 42.8 nM). The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds.
Asunto(s)
Antipsicóticos/metabolismo , Isoxazoles/metabolismo , Piperidinas/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Animales , Antipsicóticos/efectos adversos , Enfermedades de los Ganglios Basales/fisiopatología , Células CHO , Cricetinae , Humanos , Isoxazoles/efectos adversos , Cinética , Piperidinas/efectos adversos , Ratas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Receptores de Dopamina D4 , Receptores de Dopamina D5RESUMEN
HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this compound were prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A receptor affinity. The compounds were examined in vivo in animal models of potential antipsychotic activity and screened in models predictive of extrapyramidal side effect (EPS) liability. The synthesis of these compounds, details of their structure-activity relationships, and discovery of a new lead, compound 50, as well as further development of the profiles of compounds 50 and 54 are described.
Asunto(s)
Antipsicóticos/síntesis química , Compuestos de Espiro/síntesis química , Tiazoles/síntesis química , Animales , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Unión Competitiva , Células CHO , Línea Celular , Cricetinae , Humanos , Masculino , Estructura Molecular , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Receptores de Dopamina D4 , Receptores de Serotonina/metabolismo , Espiperona/metabolismo , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacología , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/metabolismo , Tiazoles/farmacología , TiazolidinasRESUMEN
Iloperidone {HP 873: 1-[4-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3-methoxyphenyl]ethanone} is a dopamine (D2)/serotonin (5-HT2) receptor antagonist with the preclinical profile of an atypical antipsychotic based on biochemical studies in rats. Iloperidone significantly increased dopa accumulation, an index of dopamine turnover in response to D2 receptor blockade, at doses from 0.3 to 10 mg/kg i.p. in the striatum and from 1 to 10 mg/kg in the nucleus accumbens. Blockade of dopaminergic presynaptic autoreceptors was measured by the reversal of apomorphine-inhibition of gamma-butyrolactone-induced dopa synthesis. Iloperidone did not significantly reverse the apomorphine inhibition of gamma-butyrolactone-induced dopa synthesis at any of the doses tested (0.3-10 mg/kg i.p.). In ex vivo receptor autoradiography studies, a 30-min pretreatment with iloperidone (2.5-20 mg/kg i.p.) inhibited the binding of [3H]spiperone to cortical and subcortical 5-HT2 receptors by 42 to 94%, in contrast to only 1 to 15% inhibition of [3H]spiperone binding to D2 receptors in the nucleus accumbens and striatum. Iloperidone, at 2.5 mg/kg i.p., inhibited 5-HT2 receptor binding by 54 to 62% at 4-hr post-treatment, whereas there was negligible inhibition of D2 receptors. Chronic treatment with 5 mg/kg i.p. of iloperidone for 19 days significantly decreased the number of 5-HT2 receptors in the frontal cortex with no change in receptor affinity. D2 receptor number and affinity were unchanged in the nucleus accumbens and six regions of the striatum. In summary, iloperidone is a 5-HT and dopamine receptor antagonist with weak activity at presynaptic dopamine autoreceptors. Potent 5-HT2 receptor antagonism may be an important component in the preclinical profile of iloperidone as a potential atypical antipsychotic.
Asunto(s)
Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Isoxazoles/farmacología , Piperidinas/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Apomorfina/farmacología , Autorradiografía , Dihidroxifenilalanina/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
Examination of HP 184, [N-n-propyl)-N-(3-fluoro-4-pyridinyl) -1H-3-methylindodel-1-amine hydrochloride], in a variety of tests for serotonergic activity revealed some unique properties of this compound. We report here that 100 microM HP 184 enhanced spontaneous release of [3H]serotonin (5-HT) from rat hippocampal slices. This release was independent of the uptake carrier. In vivo assays confirmed that HP 184 (20 mg/kg, i.p.) lacked significant interactions at the norepinephrine (NE) or 5-HT uptake carrier itself. Notably, HP 184 (15 mg/kg, i.p.) reduced drinking behavior in schedule-induced polydipsic (SIP) rats. We previously reported that some selective 5-HT reuptake inhibitors decrease SIP 30-40% after a 14-21 day treatment. In the current study, HP 184 decreased SIP beginning with the first treatment, and this reduction (30%) was maintained for 28 days. We further investigated HP 184 and serotonin metabolite levels. One hour after i.p. administration of 30 mg/kg HP 184, the ratio of whole brain 5-hydroxyindolacetic acid (5-HIAA) to 5-HT was increased, suggesting serotonergic activation. Under these conditions, the brain:plasma ratio of HP 184 was approximately 2:1, with brain concentrations of 1.6 micrograms/gram. We speculate that the spontaneous release effects of HP 184 may be responsible for the behavioral effects observed.
Asunto(s)
Aminas Biogénicas/metabolismo , Encéfalo/metabolismo , Conducta de Ingestión de Líquido/efectos de los fármacos , Hipocampo/metabolismo , Indoles/farmacología , Piridinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , 5-Hidroxitriptófano/toxicidad , Animales , Blefaroptosis/inducido químicamente , Blefaroptosis/prevención & control , Encéfalo/efectos de los fármacos , Sinergismo Farmacológico , Fenfluramina/farmacología , Hipocampo/efectos de los fármacos , Ácido Hidroxiindolacético/metabolismo , Técnicas In Vitro , Indoles/farmacocinética , Masculino , Ratones , Norepinefrina/metabolismo , Piridinas/farmacocinética , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , TetrabenazinaRESUMEN
The aim of the present paper is to report on the adrenergic and serotonergic effects of besipirdine (HP 749) in vivo and to discuss its potential use in the treatment of obsessive compulsive disorder. Besipirdine inhibited biogenic amine uptake in vitro. It prevented tetrabenazine-induced ptosis in mice and potentiated the 5-hydroxytryptophan-induced serotonin syndrome in rats. Furthermore, it decreased schedule-induced polydipsic behavior in rats. Schedule-induced polydipsia may be a model for obsessive compulsive disorder. Previous results from our group have shown that certain selective serotonin reuptake inhibitors decrease schedule-induced polydipsia after 14-21 days of treatment. Besipirdine reduced schedule-induced polydipsic behavior immediately and this reduction lasted throughout the duration of the experiment (29 days).
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Indoles/farmacología , Piridinas/farmacología , Simpaticolíticos/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Aminas Biogénicas/metabolismo , Blefaroptosis/inducido químicamente , Blefaroptosis/prevención & control , Desipramina/farmacología , Femenino , Fluoxetina/farmacología , Hipocampo/metabolismo , Técnicas In Vitro , Indoles/farmacocinética , Masculino , Ratones , Inhibidores de la Captación de Neurotransmisores/farmacología , Piridinas/farmacocinética , Ratas , Ratas Wistar , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Esquema de Refuerzo , Agonistas de Receptores de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Simpaticolíticos/farmacocinética , Sinaptosomas/metabolismoRESUMEN
A series of benzisoxazole- and benzisothiazole-3-carboxamides has been prepared and tested for potential antipsychotic activity. In general, the compounds showed an affinity for dopamine D2 and serotonin 5HT2A and 5HT1A receptors. Several members of this series have demonstrated activity in animal models predictive of potential antipsychotic activity. In addition, compounds 18, 19, 22, 27, 28, 43, and 44 have also shown a potential for reduced EPS liability as suggested by the ratio of activity seen in mesolimbic-mediated vs nigrostriatal-mediated behavioral assays.