RESUMEN
The synthesis and structure-activity relationships of 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives were investigated at the dopamine transporter (DAT), the serotonin transporter (SERT) and norepinephrine transporter (NET). The rigid ethylidenyl-8-azabicyclic[3.2.1]octane skeleton imparted modestly stereoselective binding and uptake inhibition at the DAT. Additional structure-activity studies provided a transporter affinity profile that was reminiscent of the structure-activity of GBR 12909. From these studies, the 8-cyclopropylmethyl group has been identified as a unique moiety that imparts high SERT/DAT selectivity. In this study the 8-cyclopropylmethyl derivative 22e (DAT K(i) of 4.0 nM) was among the most potent compounds of the series at the DAT and was the most DAT selective ligand of the series (SERT/DAT: 1060). Similarly, the 8-chlorobenzyl derivative 22g (DAT K(i) of 3.9 nM) was found to be highly selective for the DAT over the NET (NET/DAT: 1358).
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Octanos/química , Octanos/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of benzyl esters of meperidine and normeperidine were synthesized and evaluated for binding affinity at serotonin, dopamine and norepinephrine transporters. The 4-methoxybenzyl ester 8b and 4-nitrobenzyl ester 8c in the meperidine series and 4-methoxybenzyl ester 14a in the normeperidine series exhibited low nanomolar binding affinities at the SERT (K(i) values <2nM) and high SERT selectivity (DAT/SERT >1500 and NET/SERT >1500).
Asunto(s)
Meperidina/análogos & derivados , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Ésteres , Ligandos , Meperidina/síntesis química , Meperidina/química , Meperidina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
A series of 3-arylnortrop-2-enes and 3alpha-arylmethoxy-3beta-arylnortropanes were synthesized and evaluated for binding affinity at monoamine transporters. The 3-(3,4-dichlorophenyl)nortrop-2-ene (6e) exhibited high affinity for the SERT (K(i)=0.3 nM). The 3alpha-arylmethoxy-3beta-arylnortropanes were generally SERT selective with the 3alpha-(3.4-dichlorophenylmethoxy)-3betaphenylnortrop-2-ene (7c) possessing subnanomolar potency (K(i)=0.061 nM). However, 3alpha-(3,4-dichlorophenylmethoxy)-3beta-phenylnortrop-2-ene (7b) exhibited high affinity at all three transporters [(DAT K(i)=22 nM), (SERT K(i)=6 nM) and (NET K(i)=101 nM)].