ABSTRACT
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.
Subject(s)
Carrier Proteins/drug effects , Cocaine/antagonists & inhibitors , Mazindol/pharmacology , Membrane Glycoproteins , Membrane Transport Proteins , Nerve Tissue Proteins , Animals , Binding Sites , Binding, Competitive , Carrier Proteins/metabolism , Cocaine/analogs & derivatives , Cocaine/metabolism , Cocaine/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine Plasma Membrane Transport Proteins , Dopamine Uptake Inhibitors/metabolism , Dopamine Uptake Inhibitors/pharmacology , In Vitro Techniques , Mazindol/analogs & derivatives , RatsABSTRACT
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.
Subject(s)
Antineoplastic Agents , Isoquinolines/pharmacology , Platelet Membrane Glycoproteins/antagonists & inhibitors , Receptors, Cell Surface , Receptors, G-Protein-Coupled , Animals , Binding, Competitive , Humans , In Vitro Techniques , Isoquinolines/chemical synthesis , Magnetic Resonance Spectroscopy , Mice , Platelet Activating Factor/metabolism , Platelet Membrane Glycoproteins/metabolism , Tumor Cells, Cultured/drug effectsABSTRACT
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.
Subject(s)
Isoquinolines/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Platelet Membrane Glycoproteins/antagonists & inhibitors , Pyridines/pharmacology , Receptors, Cell Surface , Receptors, G-Protein-Coupled , Thiophenes/pharmacology , Animals , Binding, Competitive , Bronchoconstriction/drug effects , Guinea Pigs , Humans , Isoquinolines/chemical synthesis , Platelet Membrane Glycoproteins/metabolism , Pyridines/chemical synthesis , Structure-Activity Relationship , Thienopyridines , Thiophenes/chemical synthesisABSTRACT
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.
Subject(s)
Antineoplastic Agents , Phospholipid Ethers/pharmacology , Animals , Cell Division/drug effects , Humans , In Vitro Techniques , Macrophages/drug effects , Mice , Molecular Structure , Phospholipid Ethers/chemical synthesis , Phospholipid Ethers/chemistry , Platelet Aggregation/drug effects , Sarcoma, Experimental/drug therapy , Tumor Cells, Cultured/drug effectsABSTRACT
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.
