RESUMEN
SAR around a known molecule with dual 5-HT(1D) antagonist and 5-HT(transporter) inhibitory activity has led to the discovery of molecules with improved dual activity and reduced cross-reactivity toward other aminergic receptors (5-HT(1B), alpha(1), and D(2)).
Asunto(s)
Antidepresivos/farmacología , Naftalenos/química , Piperazinas/farmacología , Receptor de Serotonina 5-HT1D/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Antidepresivos/síntesis química , Relación Dosis-Respuesta a Droga , Cobayas , Cinética , Modelos Químicos , Piperazinas/síntesis química , Receptor de Serotonina 5-HT1D/metabolismo , Antagonistas de la Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.
Asunto(s)
Alcoholes/química , Morfolinas/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Cristalografía por Rayos X , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Morfolinas/químicaRESUMEN
Potent and selective ligands of the alpha7 nicotinic acetylcholine receptor are required to understand the pharmacological effect of alpha7 activation. A common cross-reactivity occurs with serotonergic 5-HT3 receptors with which alpha7 receptors have a high sequence homology. We demonstrate that certain quinuclidine 3-biaryl carboxamides are high affinity alpha7 ligands with an excellent binding selectivity over 5-HT3 receptors.
Asunto(s)
Amidas/síntesis química , Quinuclidinas/síntesis química , Receptores Nicotínicos/química , Receptores de Serotonina 5-HT3/química , Amidas/química , Reacciones Cruzadas , Sistemas de Liberación de Medicamentos , Humanos , Ligandos , Unión Proteica , Quinuclidinas/química , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and advanced intermediates for SAR expansion.
Asunto(s)
Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/fisiología , Quinolinas/química , Quinolinas/farmacología , Cromatografía Líquida de Alta Presión , Inhibidores de la Captación de Neurotransmisores/química , Relación Estructura-ActividadRESUMEN
Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Morfolinas/síntesis química , Norepinefrina/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores de Captación Adrenérgica/farmacología , Aminas Biogénicas/antagonistas & inhibidores , Aminas Biogénicas/metabolismo , Humanos , Morfolinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.