Michele Patricia Kliemann

Serotonergic neurotransmission mediates hypothermia induced by the N-phenylpiperazine antipsychotic prototypes LASSBio-579 and LASSBio-581

Previous studies have demonstrated that LASSBio-579 and LASSBio-581, two N-phenylpiperazine derivatives designed for the treatment of schizophrenia, are presynaptic dopamine D(2) receptor agonists that induce a hypothermic effect in mice that is not mediated by dopamine receptor activation. The aim of the present study was to investigate possible serotonergic mechanisms underlying hypothermia induced by LASSBio-579 and LASSBio-581 in CF1 mice. The reduction in core temperature was dose-dependent (15-60 mg/kg, i.p.) and occurred by the oral route (30 mg/kg). Pretreatment with haloperidol (4 mg/kg, i.p.) resulted in a synergistic hypothermic effect. Pretreatment with (+/-)DOI (0.25 mg/kg, i.p.), a serotonin 5-HT(2A/C) receptor agonist, reduced the hypothermic effect induced by LASSBio-579 and LASSBio-581 at 15 and 30 mg/kg, i.p. In contrast, (+/-)DOI enhanced the hypothermia induced by both compounds at 60 mg/kg, i.p. The serotonin 5-HT1A antagonist WAY 100635 (0.05 mg/kg, s.c.) abolished the hypothermia induced by LASSBio-579 and diminished the hypothermia induced by LASSBio-581. Pretreatment with LASSBio579 (30 and 60 mg/kg, i.p.) and LASSBio-581 (60 mg/kg, i.p.) reduced the number of head-twitches induced by (+/-)DOI (2.5 mg/kg, i.p.). The ear-scratch response induced by (+/-)DOI was inhibited by both LASSBio-579 and LASSBio-581 at 60 mg/kg, i.p. These results indicate that LASSBio-579 and LASSBio-581 have mechanisms of action through the serotonergic neurotransmitter system.

Hypnotic effect of ecdysterone isolated from Pfaffia glomerata (Spreng.) Pedersen

Neste trabalho foi avaliado, em roedores, o efeito depressor das fracoes cloroformio (CHCl3), acetato de etila (EtOAc) e n-butanol, obtidas das partes subterrâneas de Pfaffia glomerata, empregando-se o teste de tempo de sono barbiturico como referencia. Somente a fracao lipofilica (CHCl3:EtOAc, 1:1, m/m) (i.p. 500 mg/kg; v.o. 1000 mg/kg) potenciou o tempo de sono induzido por pentobarbital. A ecdisterona foi isolada e identificada como constituinte majoritario (1,4% m/m) desta fracao, atraves de cromatografia liquida de alta eficiencia e metodos espectroscopicos, respectivamente. Este composto potenciou o tempo de sono barbiturico (100 mg/kg, i.p.; 400 mg/kg, v.o), sem causar hipotermia. Nestas mesmas doses, a ecdisterona nao alterou a performance dos animais no rota-rod, esquiva inibitoria e labirinto em cruz-elevado, alem de nao alterar o padrao de convulsoes induzidas por pentilenotetrazol. Este perfil indica que esta substância, nestas doses, nao apresenta perfil ansiolitico ou neurotoxico. Estes resultados indicam que a ecdisterona e o componente responsavel pela acao hipnotica apresentada pela fracao lipofilica obtida das partes subterrâneas de P. glomerata.

Discovery of novel heteroarylazoleN-phenylpiperazine prototypes candidates to atypic antipsychotic drugs

This work describes the discovery of new N-phenylpiperazine prototypes belonging to pyrazole series, i.e. LASSBio-579 (10a), or to 1,2,3-triazole series, represented by LASSBio-581 (10c), which were designed from the structural simplification of the atypical antipsychotic drug clozapine (8). The evaluation of the affinity and intrinsic activity profiles of LASSBio-579 and LASSBio-581 indicate its ability to bind dopamine receptors from D2-like family, acting as pre-synaptic agonists. Additionally, the investigation of the antipsychotic properties of these two prototypes in behavioral models has confirmed its effectiveness, which is also dependent on the modulation of serotoninergic receptors 5-HT2A and 5-HT1A. The pronounced antipsychotic effect evidenced for these N-phenylpiperazine derivatives through in vivo pharmacological assays confirmed their importance as new neuroactive drug-candidate prototypes for the treatment of schizophrenia.