RESUMEN

A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.

Asunto(s)

Amidas/síntesis química , Benzamidas/síntesis química , Imidazoles/síntesis química , Indoles/síntesis química , Pirroles/síntesis química , Alcaloides de Pirrolicidina/síntesis química , Agonistas del Receptor de Serotonina 5-HT4 , Antagonistas del Receptor de Serotonina 5-HT4 , Amidas/química , Amidas/farmacología , Animales , Benzamidas/química , Benzamidas/farmacología , Bradicardia/prevención & control , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Esófago/efectos de los fármacos , Esófago/fisiología , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , Femenino , Vaciamiento Gástrico/efectos de los fármacos , Cobayas , Imidazoles/química , Imidazoles/farmacología , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Antro Pilórico/efectos de los fármacos , Antro Pilórico/fisiología , Pirroles/química , Pirroles/farmacología , Alcaloides de Pirrolicidina/química , Alcaloides de Pirrolicidina/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Relación Estructura-Actividad