RESUMEN
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.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacocinética , Animales , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Semivida , Humanos , Microsomas/metabolismo , Modelos Animales , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Multimerización de Proteína/fisiología , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transducción de Señal/fisiología , Animales , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/fisiología , Células HEK293 , Humanos , Multimerización de Proteína/efectos de los fármacos , Ratas , Ratas Wistar , Receptor Cross-Talk/fisiología , Receptor de Serotonina 5-HT2A/fisiología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacocinética , Antagonistas de los Receptores de Hormonas Antidiuréticas , Indoles/síntesis química , Indoles/farmacocinética , Animales , Antidepresivos/química , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Indoles/química , Indoles/farmacología , Estructura Molecular , Oxindoles , Unión Proteica/efectos de los fármacos , RatasRESUMEN
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.
Asunto(s)
Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibición Psicológica , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Línea Celular Transformada , Conducta de Elección/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Indoles/farmacología , Masculino , Nitrilos/farmacología , Piperidinas/farmacología , Unión Proteica/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Receptores de Dopamina D3/antagonistas & inhibidores , Tetrahidroisoquinolinas/farmacologíaRESUMEN
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.
Asunto(s)
Antipsicóticos/farmacología , Apomorfina/farmacología , Benzopiranos/farmacología , Agonistas de Dopamina/farmacología , Inhibición Psicológica , Oxazinas/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica/métodos , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Nitrilos/farmacología , Ratas , Ratas Wistar , Tetrahidroisoquinolinas/farmacologíaRESUMEN
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.
Asunto(s)
Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Receptores de Dopamina D3/antagonistas & inhibidores , Disponibilidad Biológica , Antagonistas de Dopamina/síntesis química , Humanos , Microsomas Hepáticos/metabolismo , Pirimidinonas/síntesis química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas de Dopamina/farmacología , Hipocampo/fisiología , Inhibición Neural/efectos de los fármacos , Receptores de Dopamina D3/antagonistas & inhibidores , Reflejo de Sobresalto/efectos de los fármacos , Análisis de Varianza , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Hipocampo/efectos de los fármacos , Hipocampo/lesiones , Ácido Iboténico/toxicidad , Masculino , Ratones , Ratones Endogámicos DBA , Piperazinas/farmacología , RatasRESUMEN
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.
Asunto(s)
Benzazepinas/síntesis química , Antagonistas de Dopamina/síntesis química , Quinolonas/síntesis química , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Modelos Moleculares , Estructura Molecular , Quinolonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas de Dopamina/síntesis química , Pirimidinonas/síntesis química , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Benzopiranos/antagonistas & inhibidores , Antagonistas de Dopamina/farmacología , Modelos Químicos , Oxazinas/antagonistas & inhibidores , Pirimidinonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antidepresivos/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Antidepresivos/química , Antidepresivos/farmacología , Humanos , Indoles/química , Indoles/farmacología , Cinética , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
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.