RESUMEN
Cyclopentylamine 4 was identified as a potent dual NK1R antagonist-SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.
Asunto(s)
Ciclopentanos/química , Antagonistas del Receptor de Neuroquinina-1/química , Receptores de Neuroquinina-1/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Administración Oral , Animales , Cristalografía por Rayos X , Ciclopentanos/síntesis química , Ciclopentanos/farmacología , Evaluación Preclínica de Medicamentos , Gerbillinae , Humanos , Conformación Molecular , Actividad Motora/efectos de los fármacos , Antagonistas del Receptor de Neuroquinina-1/metabolismo , Antagonistas del Receptor de Neuroquinina-1/farmacología , Unión Proteica , Receptores de Neuroquinina-1/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
NMDA receptor hypofunction is hypothesized to contribute to cognitive deficits associated with schizophrenia. Since direct activation of NMDA receptors is associated with serious adverse effects, modulation of the NMDA co-agonists, glycine or D-serine, represents a viable alternative therapeutic approach. Indeed, clinical trials with glycine and D-serine have shown positive results, although concerns over toxicity related to the high-doses required for efficacy remain. Synaptic concentrations of D-serine and glycine are regulated by the amino acid transporter alanine serine cysteine transporter-1 (asc-1). Inhibition of asc-1 would increase synaptic D-serine and possibly glycine, eliminating the need for high-dose systemic D-serine or glycine treatment. In this manuscript, we characterize Compound 1 (BMS-466442), the first known small molecule inhibitor of asc-1. Compound 1 selectively inhibited asc-1 mediated D-serine uptake with nanomolar potency in multiple cellular systems. Moreover, Compound 1 inhibited asc-1 but was not a competitive substrate for this transporter. Compound 1 is the first reported selective inhibitor of the asc-1 transporter and may provide a new path for the development of asc-1 inhibitors for the treatment of schizophrenia.
Asunto(s)
Sistema de Transporte de Aminoácidos y+/antagonistas & inhibidores , Agonistas de Aminoácidos Excitadores/farmacología , Histidina/análogos & derivados , Indoles/síntesis química , Indoles/farmacología , Receptores de N-Metil-D-Aspartato/agonistas , Aminoácidos/metabolismo , Animales , Línea Celular , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Glicina/metabolismo , Histidina/síntesis química , Histidina/farmacología , Humanos , Ratas , Ratas Sprague-Dawley , Serina/metabolismo , Bibliotecas de Moléculas Pequeñas , Sinaptosomas/metabolismoRESUMEN
Recent genetic evidence suggests that the diacylglycerol lipase (DAGL-α) isoform is the major biosynthetic enzyme for the most abundant endocannabinoid, 2-arachidonoyl-glycerol (2-AG), in the central nervous system. Revelation of its essential role in regulating retrograde synaptic plasticity and adult neurogenesis has made it an attractive therapeutic target. Therefore, it has become apparent that selective inhibition of DAGL-α enzyme activity with a small molecule could be a strategy for the development of novel therapies for the treatment of disease indications such as depression, anxiety, pain, and cognition. In this report, the authors present the identification of small-molecule inhibitor chemotypes of DAGL-α, which were selective (≥10-fold) against two other lipases, pancreatic lipase and monoacylglycerol lipase, via high-throughput screening of a diverse compound collection. Seven chemotypes of interest from a list of 185 structural clusters, which included 132 singletons, were initially selected for evaluation and characterization. Selection was based on potency, selectivity, and chemical tractability. One of the chemotypes, the glycine sulfonamide series, was prioritized as an initial lead for further medicinal chemistry optimization.