RESUMEN
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
Asunto(s)
Benzoxazoles/farmacocinética , Indoles/farmacocinética , Trastornos de la Memoria/tratamiento farmacológico , Agonistas Muscarínicos/farmacocinética , Nootrópicos/farmacocinética , Receptor Muscarínico M1/metabolismo , Animales , Benzoxazoles/química , Benzoxazoles/uso terapéutico , Encéfalo/metabolismo , Indoles/química , Indoles/uso terapéutico , Agonistas Muscarínicos/química , Agonistas Muscarínicos/uso terapéutico , Nootrópicos/química , Nootrópicos/uso terapéutico , Oxindoles , RatasRESUMEN
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Asunto(s)
Quinolinas/farmacología , Receptores de Serotonina 5-HT1/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Ligandos , Quinolinas/administración & dosificación , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.