RESUMEN
Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Analgésicos/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Imidazoles/farmacología , Isoindoles/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Analgésicos/farmacocinética , Animales , Antidepresivos/farmacocinética , Monoaminas Biogénicas/metabolismo , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Imidazoles/farmacocinética , Isoindoles/farmacocinética , Masculino , Ratones , Microdiálisis , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Natación , Sed/efectos de los fármacosRESUMEN
The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.1 nM), potent D(2) partial agonist activity (EC(50), 0.38 nM; E(max), 30%), and complete block of the serotonin transporter (IC(50), 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID(50), 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D(2) partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D(2) receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.
Asunto(s)
Antidepresivos/farmacología , Antipsicóticos/farmacología , Benzoxazoles/farmacología , Agonistas de Dopamina/farmacología , Indenos/farmacología , Receptores de Dopamina D2/agonistas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Antidepresivos/química , Antipsicóticos/química , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Benzoxazoles/química , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Dopamina/metabolismo , Agonistas de Dopamina/química , Evaluación Preclínica de Medicamentos , Humanos , Indenos/química , Masculino , Ratones , Ratones Endogámicos , Microdiálisis , Actividad Motora/efectos de los fármacos , Unión Proteica , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Serotonina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT2 , Inhibidores Selectivos de la Recaptación de Serotonina/química , TransfecciónRESUMEN
Recent studies have reported that estrogen has antidepressant-like effects in animal models. In this study we used the highly selective ER beta agonist, WAY-200070, to examine the role of ER beta activation on brain neurochemistry and activity in antidepressant and anxiolytic models in male mice. Within 15 min of administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ER beta receptors from the cytosol. WAY-200070 also increased c-fos activation 4h, but not 15 min after administration. Both nuclear translocation and c-fos induction effects of WAY-200070 demonstrate that WAY-200070 has bound to estrogen receptors and triggered downstream events. The absence of these effects in the ER beta KO mice confirms that WAY-200070 was targeting ER beta. Administration of WAY-200070 (30 mg/kg s.c.) produced a delayed approximately 50% increase in dopamine in the striatum of wild type mice. The effect was significant and maintained from 90 to 240 min. This increase was absent in ER beta KO mice. In wild type mice, WAY-200070 (30 mg/kg s.c.) also produced a delayed and transient approximately 100% increase in 5-HT. To further investigate the role of ER beta receptors on serotonergic function, 5-HTP accumulation was measured. ER beta KO mice were found to have reduced frontal cortex levels of 5-HTP, indicating reduced tryptophan hydroxylase activity. WAY-200070 (3-30 mg/kg s.c.) was also tested in behavioural models. WAY-200070 (30 mg/kg s.c.) reduced immobility time in the mouse tail suspension test indicating an antidepressant-like effect. WAY-200070 (30 mg/kg) showed anxiolytic-like effects in the four-plate test (increased punished crossings) and stress-induced hyperthermia (attenuation of hyperthermic response). The effects of the selective ER beta agonist, WAY-200070, on dopamine and serotonin, the anxiolytic-like and antidepressant-like effects as well as the genotype specific effects on neurochemistry support that positive modulation of ER beta function may provide a novel treatment for affective disorders.