RESUMEN
The recent publication of X-ray structures of SERT includes structures with the potent antidepressant S-Citalopram (S-Cit). Earlier predictions of ligand binding at both a primary (S1) and an allosteric modulator site (S2), were confirmed. We provide herein examples of a series of Citalopram analogs, showing distinct structure-activity relationship (SAR) at both sites that is independent of the SAR at the other site. Analogs with a higher affinity and selectivity than benchmark R-Citalopram (R-Cit) for the S2 versus the S1 site were identified. We deploy structural and computational analyses to explain this SAR and demonstrate the potential utility of the newly emerging X-ray structures within the neurotransmitter:sodium Symporter family for drug design.
Asunto(s)
Citalopram/análogos & derivados , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sitio Alostérico , Sitios de Unión , Citalopram/síntesis química , Citalopram/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
Asunto(s)
Antipsicóticos/química , Ligandos , Quinolonas/química , Receptor Muscarínico M1/agonistas , Receptores de Dopamina D2/agonistas , Antipsicóticos/síntesis química , Antipsicóticos/farmacocinética , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Quinolonas/síntesis química , Quinolonas/farmacocinética , Receptor Muscarínico M1/metabolismo , Receptores de Dopamina D2/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.