RESUMEN
BACKGROUND: A plethora of indirect findings suggests that mood disorders may be caused by or result in structural changes in the brain, namely decreased hippocampal cell proliferation. METHODS: To test for these hypotheses, we used a rat model of depression, learned helplessness. Moderate unpredictable and inescapable foot shocks induced learned helplessness only in a portion of the rats. Rats that showed helpless behavior were compared to those behaving normally after inescapable shock. Proliferating cells in the dentate gyrus were labeled with BrdU (bromodeoxyuridine). RESULTS: Helpless behavior appeared before the decrease of dentate gyrus cell proliferation was maximal. Cell proliferation was decreased to the same extent in animals that developed helplessness as those that were not helpless. Furthermore, immobilization stress, which reduced the rate of cell proliferation, did not induce learned helplessness. CONCLUSION: These results are in line with reports that the rate of dentate gyrus cell proliferation is acutely down-regulated by stress, but the development of helpless behavior does not correlate with this process. Further studies will have to clarify if during learned helpless behavior neurogenesis is impaired by altered differentiation or survival of cells.
Asunto(s)
Giro Dentado/patología , Desamparo Adquirido , Análisis de Varianza , Animales , Conducta Animal , Bromodesoxiuridina/farmacocinética , Recuento de Células , División Celular , Giro Dentado/metabolismo , Giro Dentado/efectos de la radiación , Electrochoque/métodos , Inmovilización , Inmunohistoquímica , Masculino , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The influence of aromatic substitution on a newly discovered class of inhibitors of dipeptidyl peptidase IV was investigated. A 10(5)-fold increase in potency was achieved by the optimization of aromatic substituents in a parallel chemistry program. The observed SAR could be explained by an X-ray structure of the protein-ligand complex.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Glicoproteínas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Pirimidinas/química , Adenosina Desaminasa/metabolismo , Glicoproteínas/metabolismo , Inhibidores de Proteasas/metabolismo , Pirimidinas/metabolismoRESUMEN
In a novel series of DPP-IV inhibitors, a large increase of inhibitory activity was achieved by optimisation of aromatic substituents and conformational restriction.
Asunto(s)
Aminas/química , Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Piridinas/síntesis química , Células Cultivadas , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Hidrocarburos Aromáticos/química , Hidrocarburos Aromáticos/farmacología , Concentración 50 Inhibidora , Piridinas/metabolismo , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A recently identified DPP-IV inhibitor (1) was found to induce phospholipidosis and to inhibit CYP3A4. A small series of less lipophilic and less amphiphilic analogues was synthesized in an effort to overcome these issues. One compound from this series was equipotent to 1, did not induce phospholipidosis and showed a reduced CYP3A4 inhibition.