RESUMO
SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.
Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Antagonistas do Receptor 5-HT1 de Serotonina , 5-Hidroxitriptofano/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Contagem de Células , Dioxanos/farmacologia , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Estimulação Elétrica , Eletroquímica/métodos , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Haloperidol/farmacologia , Humanos , Imuno-Histoquímica/métodos , Técnicas In Vitro , Levodopa/metabolismo , Masculino , Microdiálise/métodos , Neurônios/efeitos dos fármacos , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/química , Receptores de Dopamina D2/química , Antagonistas da Serotonina/farmacologia , Isótopos de Enxofre/farmacocinética , Fatores de Tempo , Tropanos/farmacologiaRESUMO
In the present study, we have investigated the potential neuroprotective effects of a novel peripheral benzodiazepine binding site (PBR) ligand, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575), in models of central and peripheral neurodegeneration in vivo and its effect on steroid concentrations in plasma and nervous tissue. SSR180575 shows high affinity (IC(50), 2.5-3.5 nM) and selectivity for the rat and human PBR and potently inhibits the in vivo binding of [(3)H]alpidem to PBR in the rat brain and spleen after oral or i.p. administration (ID(50), 0.1-0.3 mg/kg). In an experimental model of motoneuron degeneration induced by facial nerve axotomy in the immature rat, SSR180575 given i.p. or orally for 8 days rescued facial motoneurons, increasing their survival by 40 to 72% at 6 and 10 mg/kg p.o. b.i.d. Moreover, in this model, SSR180575 (10 mg/kg p.o. b.i.d.) increased by 87% the number of motoneurons immunoreactive to peripherin, a type III intermediate filament, whose expression is up-regulated during nerve regeneration. SSR180575 also improved functional recovery in acrylamide-induced neuropathy in the rat when given therapeutically at 2.5 to 10 mg/kg/day p.o. Furthermore, SSR180575 (3 mg/kg i.p. b.i.d.) accelerated functional recovery of the blink reflex after local injury of the facial nerve in the rat. SSR180575 increased pregnenolone accumulation in the brain and sciatic nerve (+100% at 3 mg/kg i.p.), suggesting that its neuroprotective effects are steroid-mediated. These results indicate that PBR ligands (e.g., SSR180575) promote neuronal survival and repair in axotomy and neuropathy models and have potential for the treatment of neurodegenerative diseases (e.g., peripheral neuropathies or amyotrophic lateral sclerosis).