RESUMO
Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3â¯mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Animais , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Meia-Vida , Humanos , Microssomos/metabolismo , Modelos Animais , Ratos , Relação Estrutura-AtividadeRESUMO
Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.
Assuntos
Antidepressivos/síntese química , Antidepressivos/farmacocinética , Antagonistas dos Receptores de Hormônios Antidiuréticos , Indóis/síntese química , Indóis/farmacocinética , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Modelos Animais de Doenças , Indóis/química , Indóis/farmacologia , Estrutura Molecular , Oxindóis , Ligação Proteica/efeitos dos fármacos , RatosRESUMO
Behavioral disinhibition is a manifestation of impulsive behavior that is prominent in the psychopathology of various psychiatric disorders such as addiction, attention-deficit hyperactivity disorder, mania, and personality disorders. Impulsivity may be studied by measuring anticipatory responses made before the presentation of a food-predictive, brief light stimulus in a two-choice serial reaction time task. In such serial reaction time tasks, amphetamine has been shown to produce dose-dependent increases in premature responding in a manner dependent on dopamine D(2)-like receptor stimulation. So far, it is unknown whether it is the D(2) or D(3) receptor that is involved in this form of impulsivity. In this study, rats were trained in a two-choice serial reaction time task until baseline performance was stable. Next, effects of the dopamine D(2) preferring antagonist L-741,626 and selective D(3) antagonist SB-277011 were assessed alone and in the presence of amphetamine. Neither L-741,626 nor SB-277011 affected behavioral inhibition, although the latter significantly increased reaction time at 10 mg/kg. Amphetamine dose-dependently increased impulsivity. The effect of amphetamine was attenuated by L-741,626 (3 mg/kg), whereas SB-277011 (3 mg/kg) had no effect. Therefore, amphetamine-induced behavioral disinhibition depends on D(2), but not D(3), receptor stimulation.
Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibição Psicológica , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Linhagem Celular Transformada , Comportamento de Escolha/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Indóis/farmacologia , Masculino , Nitrilas/farmacologia , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
Rats treated with apomorphine and amphetamine display sensorimotor gating impairments, as measured by prepulse inhibition (PPI), and these impairments can be reversed by antipsychotic treatment. However, it remains unknown whether the dopamine (DA) D(3) receptor plays a role in mediating these effects on PPI, as none of these DA agonists or antipsychotics are exclusively selective at either D(2) or D(3) receptors. To address this question, the current study was designed to investigate whether antipsychotic drugs and selective D(3) antagonists could block the PPI-disruptive effects of PD 128907 (a preferential D(3) agonist) and apomorphine. We found that the effect of PD 128907 on PPI in rats could be antagonized by risperidone, clozapine, and the selective D(3) antagonists SB 277011 and A-691990, but not by raclopride or haloperidol, while the apomorphine-induced PPI deficit could be reversed by risperidone, clozapine and haloperidol, but not by SB 2770111 and A-691990. These results suggest that the D(3) receptor does not mediate apomorphine-induced disruption of PPI in rats, however, given the findings that PD 128907 elicited a PPI-disruptive effect that was blocked by selective D(3) antagonists, a role of D(3) receptor in mediating PPI in rats cannot be ruled out. The possible mechanisms of D(3) receptor involvement in PPI are discussed.
Assuntos
Antipsicóticos/farmacologia , Apomorfina/farmacologia , Benzopiranos/farmacologia , Agonistas de Dopamina/farmacologia , Inibição Psicológica , Oxazinas/farmacologia , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica/métodos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Nitrilas/farmacologia , Ratos , Ratos Wistar , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animal models such as the test of prepulse inhibition of startle response (PPI) in rodents. It has been found that antipsychotics enhanced PPI in DBA mice and reversed the PPI deficit induced by neonatal ventral hippocampal (NVH) lesions in rats. However, the relative involvement of D(3) and D(2) receptors in these effects is unknown since all antipsychotics are D(2)/D(3) antagonists with limited binding preference at D(2) receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D(3) vs D(2) receptors on PPI in DBA/2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D(2)/D(3) antagonists, haloperidol at 0.3-3 mg/kg, or risperidone at 0.3-1 mg/kg, while PPI-enhancing effects were observed after the administration of higher doses of the preferential D(3)/D(2) antagonist, BP 897 at 8 mg/kg, and the selective D(3) antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D(3) antagonist, AVE 5997 up to 30 mg/kg. The PPI deficits induced by NVH lesions were reversed by haloperidol but not by the more selective D(3) antagonists, A-437203 and AVE 5997. BP 897 enhanced PPI nonselectivity, that is, in both lesioned and nonlesioned rats. In summary, the present study indicates that PPI-enhancing effects induced by antipsychotics in DBA/2J mice and in NVH-lesioned rats are unlikely to be mediated by D(3) receptors.
Assuntos
Antagonistas de Dopamina/farmacologia , Hipocampo/fisiologia , Inibição Neural/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hipocampo/efeitos dos fármacos , Hipocampo/lesões , Ácido Ibotênico/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos DBA , Piperazinas/farmacologia , RatosRESUMO
Dopamine D2-like receptors, including D2, D3, and D4 receptors, are involved in the regulation of glomerular hyperfiltration due to diabetes mellitus. These hemodynamic alterations represent a risk factor for the later development of diabetic nephropathy. The aim of the present study was to determine whether the D3 receptor subtype modulates the diabetes-induced increase in glomerular filtration rate (GFR) in rats. Renal function was studied in Sprague-Dawley rats 14 days after induction of a moderate diabetes mellitus (DM) by streptozotocin and in non-diabetic controls (CON). Rats were orally treated either with the peripherally acting, selective dopamine D3 receptor antagonist BSF 135170 (BSF, 10 mg/kg per day for 2 weeks) or with vehicle (VHC). Perfusion-fixed kidneys were used for estimation of glomerular volume. In conscious rats, which were treated with BSF, the DM-induced increase in fluid intake, urinary output, and renal sodium excretion was significantly less pronounced than in the vehicle group (DM-VHC). In the clearance experiments, GFR in CON was about 0.84+/-0.04 ml/min per 100 g body weight. The DM-VHC group presented a significant glomerular hyperfiltration (1.09+/-0.04 ml/min per 100 g body weight). Treatment with BSF significantly lowered GFR towards levels of CON. The estimated glomerular volume was 0.73+/-0.03 x 10(6) microm3 in the CON-VHC group and 0.86+/-0.04 x 10(6) microm3 in the DM-VHC animals. Interestingly, treatment with BSF decreased the glomerular volume in both groups. Irrespective of BSF treatment, kidney wet weight related to body weight was about 36% higher in DM animals compared with CON animals. We conclude that dopamine D3 receptors represent a target for the modulation of diabetes-induced glomerular hyperfiltration. Therefore, the results encourage the testing of the possible beneficial effects of long-term D3 receptor blockade on the development of diabetic nephropathy.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Antagonistas de Dopamina/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Bovinos , Domperidona/farmacologia , Haloperidol/farmacologia , Humanos , Testes de Função Renal , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Dopamine, serotonin and glutamate play a role in the pathophysiology of schizophrenia. In the brain a functional crosstalk between the serotonin receptor 5-HT(2A) and the metabotropic glutamate receptor mGlu(2) has been demonstrated. Such a crosstalk may be mediated indirectly through neuronal networks or directly by receptor oligomerization. A direct link of the 5-HT(2A)-mGlu(2) heterocomplex formation to receptor function, i.e. to intracellular signaling, has not been fully demonstrated yet. Here we confirm the formation of 5-HT(2A)-mGlu(2) heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu(2) formed complexes with 5-HT(2B) and mGlu(5) but not 5-HT(2C) indicating that complex formation is not specific to the 5-HT(2A)-mGlu(2) pair. We studied the functional consequences of the 5-HT(2A)-mGlu(2) heterocomplex addressing cellular signaling pathways. Co-expression of receptors in HEK-293 cells had no relevant effects on signaling mediated by the individual receptors when mGlu(2) agonists, antagonists and PAMs, or 5-HT(2A) hallucinogenic and non-hallucinogenic agonists and antagonists were used. Hallucinogenic 5-HT(2A) agonists induced signaling through G(q/11), but not G(i) and thus did not lead to modulation of intracellular cAMP levels. In membranes of the medial prefrontal cortex [(3)H]-LY341495 binding competition of mGlu(2/3) agonist LY354740 was not influenced by 2,5-dimethoxy-4-iodoamphetamine (DOI). Taken together, the formation of GPCR heterocomplexes does not necessarily translate into second messenger effects. These results do not put into question the well-documented functional cross-talk of the two receptors in the brain, but do challenge the biological relevance of the 5-HT(2A)-mGlu(2) heterocomplex.
Assuntos
Multimerização Proteica/fisiologia , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Células HEK293 , Humanos , Multimerização Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor Cross-Talk/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.
Assuntos
Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Disponibilidade Biológica , Antagonistas de Dopamina/síntese química , Humanos , Microssomos Hepáticos/metabolismo , Pirimidinonas/síntese química , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of novel and selective dopamine D(3)-receptor antagonists based on a 3,4-dihydro-1H-quinolin-2-one, a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1H-quinoline-2,4-dione or a 3,4-dihydro-1H-benzo[b]azepine-2,5-dione scaffold are discussed. A706149 (2.15mg/kg, po) antagonizes PD 128907-induced huddling deficits in rat, a social interaction paradigm.
Assuntos
Benzazepinas/síntese química , Antagonistas de Dopamina/síntese química , Quinolonas/síntese química , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Modelos Moleculares , Estrutura Molecular , Quinolonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of novel highly potent and selective dopamine D(3)-receptor antagonists based on a 1H-pyrimidin-2-one scaffold are described. A-690344 antagonized PD 128907-induced huddling deficits in rat (ED(50) 6.1mg/kg po), a social interaction paradigm.
Assuntos
Antagonistas de Dopamina/síntese química , Pirimidinonas/síntese química , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzopiranos/antagonistas & inibidores , Antagonistas de Dopamina/farmacologia , Modelos Químicos , Oxazinas/antagonistas & inibidores , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.