RESUMEN
The synthesis and structure-activity relationship (SAR) study of a novel series of N-type calcium channel blockers are described. L-Cysteine derivative 2a was found to be a potent and selective N-type calcium channel blocker with IC(50) 0.63 microM on IMR-32 assay. Compound 2a showed analgesic efficacy in the rat formalin-induced pain model by intrathecal and oral administration.
Asunto(s)
Aminoácidos/farmacología , Analgésicos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/metabolismo , Aminoácidos/síntesis química , Aminoácidos/química , Aminoácidos/uso terapéutico , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/efectos de los fármacos , Modelos Animales de Enfermedad , Formaldehído , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Ratas , Relación Estructura-ActividadRESUMEN
The expression of a receptor subtype for one type of excitatory amino acid agonist, t-ACPD, was examined in developing Purkinje cells of cerebellar slices. The t-ACPD-induced responses were compared with those induced by QA in current response, single cell Ca2+ imaging and changes in the miniature currents in the same preparation. It was found that t-ACPD induced a single component of inward current, and an increase in the frequency of miniature currents associated with the presence of external Ca2+, but was ineffective at mobilizing intracellular Ca2+ even in the presence of external Ca2+. The present study suggests the expression of at least two types of metabotropic receptors in the Purkinje cell region, one of which, expressed in the Purkinje cell dendrites, is highly sensitive to QA, but relatively insensitive to t-ACPD, and the other of which is a t-ACPD-sensitive receptor expressed on the presynaptic terminals of the neurons making synapses onto Purkinje cells.
Asunto(s)
Cerebelo/fisiología , Cicloleucina/análogos & derivados , Neurotoxinas/farmacología , Células de Purkinje/fisiología , Receptores de Glutamato Metabotrópico , Receptores de Neurotransmisores/fisiología , Sinapsis/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona , Animales , Calcio/metabolismo , Cicloleucina/farmacología , Dendritas/efectos de los fármacos , Dendritas/fisiología , Dendritas/ultraestructura , Potenciales Evocados/efectos de los fármacos , Colorantes Fluorescentes , Compuestos Heterocíclicos con 3 Anillos , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Células de Purkinje/citología , Células de Purkinje/efectos de los fármacos , Quinoxalinas/farmacología , Ácido Quiscuálico/farmacología , Ratas , Receptores de Neurotransmisores/efectos de los fármacosRESUMEN
To investigate the relation between the function of Ca(2+)-activated K+ channels and phosphoinositide turnover, we have examined the physiological and pharmacological characteristics of ionotropic and metabotropic quisqualate (QA) receptors in rat cerebellar Purkinje cells during development using the slice-patch method combined with Ca2+ imaging. The typical response to QA obtained from a rat on postnatal day (PND) 21 consisted of three components: (1) a fast inactivating inward current, (2) a slow inward current, and (3) a slow outward current. The slow inward current was abolished in Ca(2+)-free medium, while the fast inactivating inward current and the slow outward current remained unaffected. The slow outward current which appeared to be activated via a metabotropic receptor was not observed in the Purkinje cell of PND 7 rat, in which dendrites were poorly developed but its amplitude increased linearly with PND. QA caused significant increases in [Ca2+]i in the fully developed dendritic region of the Purkinje cells even in Ca(2+)-free medium, suggesting a dendritic localization of the metabotropic receptors.