RESUMO
A series of novel long-chain arylpiperazines bearing a coumarin fragment was synthesized and the compounds were evaluated for their affinity at alpha(1), D(2 )and 5-HT(2A) receptors. Most of the new compounds showed high affinity for the three types of receptors alpha(1A), D(2) and 5-HT(2A) which depends, fundamentally, on the substitution of the N(4) of the piperazine ring. From the series emerged compound 6, which had an haloperidol-like profile at D(2) and 5HT(2A) receptors (pK(i) values of 7.93 and 6.76 respectively). The higher alpha(1A) receptor affinity (pA(2)=9.07) of this compound could contribute to a more atypical antipsychotic profile than the haloperidol.
Assuntos
Piperazinas/síntese química , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Algoritmos , Animais , Aorta Torácica/efeitos dos fármacos , Cumarínicos/química , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Técnicas In Vitro , Indicadores e Reagentes , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Relação Estrutura-AtividadeRESUMO
A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo[b]furan-4-ones bearing 4-(6-fluorobenzisoxazolyl)piperidine, 4-(p-fluorobenzoyl)piperidine, 4-(o-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, or linear butyro(or valero)phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D(1), D(2), D(4)) and serotonin receptors (5-HT(2A), 5-HT(2B), 5-HT(2C)), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT(2A) receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(p-fluorobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)p iperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs.
Assuntos
Antipsicóticos/síntese química , Butirofenonas/síntese química , Isoxazóis/síntese química , Piperidinas/síntese química , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Animais , Antipsicóticos/química , Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva , Butirofenonas/química , Butirofenonas/metabolismo , Butirofenonas/farmacologia , Catalepsia/induzido quimicamente , Bovinos , Corpo Estriado/metabolismo , Lobo Frontal/metabolismo , Humanos , Técnicas In Vitro , Isoxazóis/química , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Masculino , Camundongos , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Retina/metabolismoRESUMO
The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3, 4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D(1)-like and D(2)-like subtypes. All compounds showed very low D(1) affinities. This could be ascribed to the absence of a catechol nucleus or of the beta-phenyldopamine pharmacophore. Only the N-methyl-5-hydroxy- (5a), N-methyl-10-hydroxy- (6a), and N-methyl-4-bromo-10-methoxy-2,3, 12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D(2) receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)ethylamine moiety does not meet the requirements of the D(2) agonist pharmacophore: namely, the 2-(3-hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D(4) receptors, and only 5a showed low affinity for rat recombinant D(3) receptors. Analysis of the influence of Na(+) on [(3)H]spiperone binding showed that 5a displays a potential dopamine D(2) agonist profile, whereas 6a probably has a dopamine D(2) antagonist activity. The D(2) agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells.