Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

Abstract

Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinsons disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl)-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/ kg) in three experimental models: 1) blockade of amphetamine (30 mg/kg, ip)-induced stereotypy in rats; 2) the catalepsy test in mice, and 3) apomorphine (1 mg/kg, ip)-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip) and a hypothermic response (30 mg/kg, ip) which was not prevented by haloperidol (0.5 mg/kg, ip). Compound 5 (30 mg/kg, ip) also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip). Only compound 4 (30 mg/kg, ip) significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D 2 /D 3 receptors.

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

“…Metodologia sintética para a preparação dos aldeídos pirazólicos (11) e 1,2,3-triazólicos (12) funcionalizados O processo eleito para a construção dos aldeídos heteroaromáticos da série pirazólica (11) e da série 1,2,3-triazólica (12) explorou como matérias-primas as correspondentes fenil-hidrazinas (13) Por outro lado, os efeitos hipotérmico e sobre a motilidade intestinal apresentados pelas substâncias apontaram para uma ação estimulatória das funções dopaminérgicas. 15,16 Para a investigação do mecanismo de ação de LASSBio-579 (10a) e LASSBio-581 (10c) foi selecionado o modelo de aferição da temperatura corporal. Ambas as substâncias apresentaram um efeito hipotérmico dose-dependente (15 -60 mg/kg i.p.…”

“…; 30 mg/kg v.o. ), 15,16 efeito classicamente relacionado a ação de agonistas dopaminérgicos nos centros de regulação da temperatura corporal, especialmente agonistas de receptores D 2 , e.g. apomorfina (20) (Figura 5).…”

“…Além disso, o haloperidol nesta dose induziu uma redução na temperatura dos animais per se. 16 O efeito hipotérmico de altas doses de haloperidol assim como sua reversão pela pré-administração de agonistas de receptores 5-HT 2 são relatados na literatura. 17 Considerando este conjunto de dados e a grande afinidade da clozapina (8) por receptores serotoninérgicos, ficava clara a necessidade de investigar o envolvimento do sistema serotoninérgico no efeito hipotérmico evidenciado para LASSBio-579 (10a) e LASSBio581 (10c), especialmente da modulação de receptores 5-HT 2A e 5-HT 1A .…”

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

“…after the determination of basal temperature as described by Neves et al (2003). Subsequent measurements were done 15, 30, 60 and 90 min after the drug injection.…”

High performance liquid chromatography method for quantification of the N-phenylpiperazine derivative LASSBio-579 in rat plasma

“…The compounds were also assayed (dose range of 15-40 mg/kg) in three experimental models: blockage of amphetamine (30 mg/kg, ip)-induced stereotypy in rats; the catalepsy test in mice, and apomorphine (1 mg/kg, ip)-induced hypothermia in mice. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behavior 6 .…”