RESUMO
A series of halogenated (F, Cl, Br, I), pyrimido and diazepino homologs of mazindol were prepared and evaluated for their ability to displace [3H]WIN 35,428 binding and to inhibit uptake of [3H]dopamine (DA) in rat striatal tissue. All of the compounds except for the 2'-chloro (6) and 2'-bromo (16) analogs of mazindol displaced [3H]WIN 35,428 binding and inhibited [3H]DA uptake more effectively than (R)-cocaine. Structure-activity studies indicated that best inhibition of [3H]WIN 35,428 binding occurred in the imidazo series with compounds containing one or two Cl or Br atoms in the 3'- or 4'-position of the free phenyl group. Replacement of the imidazo ring by a pyrimido or diazepino ring enhanced binding inhibition. The most potent inhibitors of [3H]WIN 35,428 binding and [3H]DA uptake were 6-(3'-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-alpha]isoind ol-6-ol (23; IC50 1.0 nM; 8 x mazindol) and 7-(3',4'-dichlorophenyl)-2,3,4,5-tetrahydro-7H-diazepino[2,1-alpha ]isoindol-7-ol (28; IC50 0.26 nM; 32 x mazindol), respectively. No significant differences was found between binding and uptake inhibition. Mazindol and the pyrimido and diazepino homologs 24 and 27 showed a selectivity for the DA uptake over the serotonin (5-HT) uptake site of 5-, 250-, and 465-fold, respectively, and displayed weak or no affinity for a variety of neurotransmitter receptor sites.
Assuntos
Proteínas de Transporte/efeitos dos fármacos , Cocaína/antagonistas & inibidores , Mazindol/farmacologia , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Animais , Sítios de Ligação , Ligação Competitiva , Proteínas de Transporte/metabolismo , Cocaína/análogos & derivados , Cocaína/metabolismo , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Inibidores da Captação de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Técnicas In Vitro , Mazindol/análogos & derivados , RatosRESUMO
A series of 5-aryl-2,3-dihydroimidazo[2,1-a]isoquinolines previously reported to be platelet activating factor (PAF) receptor antagonists were evaluated for potential antitumor activity. Several compounds, such as the 5-(4'-tert-butylphenyl) (65), 5-[4'-(trimethylsilyl)phenyl] (69), and 5-(4'-cyclohexylphenyl) (71) analogs showed very good cytotoxicity against several tumor cell lines. 5-[4'-(Piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1- a]isoquinoline (SDZ 62-434, 53) was more effective on a milligram per kilogram basis than the clinical cytostatic agent edelfosine (1) in increasing survivors and decreasing tumor volume in the oral mouse Meth A fibrosarcoma assay. It was selected for further development and is currently in phase I clinical trials in cancer patients.
Assuntos
Antineoplásicos , Isoquinolinas/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Receptores de Superfície Celular , Receptores Acoplados a Proteínas G , Animais , Ligação Competitiva , Humanos , Técnicas In Vitro , Isoquinolinas/síntese química , Espectroscopia de Ressonância Magnética , Camundongos , Fator de Ativação de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
In an effort to determine the effect of modification of the imidazo[2,1-a]isoquinoline portion of the PAF-receptor antagonist SDZ 64-412 (1), several new analogs were prepared and evaluated in vitro and in vivo. One of these, 5-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenyl]-2,3-dihydroimidazo [1,2-a]thieno[2,3-c]pyridine (6) was 4-5 times more potent than 1 in inhibiting PAF-induced bronchoconstriction and hemoconcentration when administered po to the guinea pig.
Assuntos
Isoquinolinas/farmacologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Piridinas/farmacologia , Receptores de Superfície Celular , Receptores Acoplados a Proteínas G , Tiofenos/farmacologia , Animais , Ligação Competitiva , Broncoconstrição/efeitos dos fármacos , Cobaias , Humanos , Isoquinolinas/síntese química , Glicoproteínas da Membrana de Plaquetas/metabolismo , Piridinas/síntese química , Relação Estrutura-Atividade , Tienopiridinas , Tiofenos/síntese químicaRESUMO
Ether phospholipids have demonstrated both in vitro and in vivo activity against a wide variety of tumor cell lines. The known cyclic ether phospholipid, SRI 62-834, was used as the model to prepare eight novel phospholipids containing a cyclic ether. All of the compounds were as effective as ET-18-OCH3 in their ability to activate macrophage-induced cytotoxicity against the Abelson-8.1 tumor cell line but varied in their direct cytotoxic effects. One of the new compounds, SDZ 62-406, was selected for in vivo studies and showed oral and i.v. activity in the mouse MethA fibrosarcoma model in the same range as ET-18-OCH3. No correlation was found between the direct or macrophage-activated cytotoxicity and the ability of the compounds to inhibit or promote platelet-activating factor (PAF)-induced aggregation of human platelets.
Assuntos
Antineoplásicos , Éteres Fosfolipídicos/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Humanos , Técnicas In Vitro , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Éteres Fosfolipídicos/síntese química , Éteres Fosfolipídicos/química , Agregação Plaquetária/efeitos dos fármacos , Sarcoma Experimental/tratamento farmacológico , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
A series of 5-aryl-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinolin-5-ols was prepared and evaluated for potential antidepressant activity in the reserpine-induced hypothermia model and selected central nervous system and autonomic activity tests. Several members of the series, notably the 4-chloro- and 4-fluorophenyl analogues, demonstrated pharmacological activity in the range of imipramine. Both compounds provided a marked potentiation of the 5-hydroxytryptophan-facilitated monosynaptic spike in the spinal cat preparation.