RESUMO
A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A. Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned avoidance response and a pro-psychotic phencyclidine hyperactivity model.
Assuntos
Hidrazonas/química , Hidrazonas/uso terapêutico , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/enzimologia , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Hidrazonas/farmacocinética , Camundongos , Inibidores de Fosfodiesterase/farmacocinética , Relação Estrutura-AtividadeRESUMO
Cyclic nucleotide phosphodiesterases (PDEs) are represented by a large superfamily of enzymes. A series of hydrazone-based inhibitors was synthesized and shown to be novel, potent, and selective against PDE10A. Optimized compounds of this class were efficacious in animal models of schizophrenia and may be useful for the treatment of this disease.
Assuntos
Hidrazonas/química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Quinolinas/química , Animais , Modelos Animais de Doenças , Humanos , Hidrazonas/farmacocinética , Hidrazonas/uso terapêutico , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Ratos , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Neuromedin U (NMU) is a highly conserved neuropeptide with a variety of physiological functions mediated by two receptors, peripheral NMUR1 and central nervous system NMUR2. Here we report the generation and phenotypic characterization of mice deficient in the central nervous system receptor NMUR2. We show that behavioral effects, such as suppression of food intake, enhanced pain response, and excessive grooming induced by intracerebroventricular NMU administration were abolished in the NMUR2 knockout (KO) mice, establishing a causal role for NMUR2 in mediating NMU's central effects on these behaviors. In contrast to the NMU peptide-deficient mice, NMUR2 KO mice appeared normal with regard to stress, anxiety, body weight regulation, and food consumption. However, the NMUR2 KO mice showed reduced pain sensitivity in both the hot plate and formalin tests. Furthermore, facilitated excitatory synaptic transmission in spinal dorsal horn neurons, a mechanism by which NMU stimulates pain, did not occur in NMUR2 KO mice. These results provide significant insights into a functional dissection of the differential contribution of peripherally or centrally acting NMU system. They suggest that NMUR2 plays a more significant role in central pain processing than other brain functions including stress/anxiety and regulation of feeding.