RESUMEN
New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Azetidinas/farmacología , Neuronas/fisiología , Agonistas Nicotínicos/farmacología , Dolor , Piridinas/farmacología , Receptores Nicotínicos/fisiología , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/química , Animales , Azetidinas/administración & dosificación , Azetidinas/química , Diástole/efectos de los fármacos , Femenino , Humanos , Inyecciones Intraperitoneales , Cinética , Ratones , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Neuroblastoma , Neuronas/efectos de los fármacos , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/química , Oocitos/fisiología , Dimensión del Dolor , Piridinas/administración & dosificación , Piridinas/química , Ratas , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , XenopusRESUMEN
2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.