Dibenzazepine Derivatives Research Articles

Effect of some phenothiazine and dibenzazepime derivatives on the muscarinic cholinergic system

Interactions of some dialkylaminoalkyl (DAL) and dialkylaminoacyl (DAC) derivatives of phenothiazine and dibenzazepine with muscarinic cholinergic receptors (MR) of rabbit striatum and heart and rat brain were investigated. DAC derivatives were more active at brain and heart MR in some cases. The most active preparation was G-512, DA-analogue of chlorpromazine. Some cardiotropic properties of antianginal preparation nonachlazine may be connected with its central antimuscarinic activity.

Changes of Ligand Binding After Membrane Phosphorylation

Phosphorylation of synaptic plasma brain membranes (SPM) causes a decrease of the specific binding of demethylated tricyclic antidepressants (TCA) and changes the affinity of 3H-imipramine and 3H-desmethylimipramine binding. The decrease of TCA binding was found also in lymphocyte membranes. In platelet membranes a decreased binding was found only with demethylated dibenzazepine derivatives. Bmax and Kd values are also decreased in the presence of phosphatidic acid or alpha-glycerolphosphate.

Methylated and Demethylated Tricyclic Antidepressants and Their Binding to Cell Membranes

We studied the binding of methylated and demethylated tricyclic antidepressants (TCA) to synaptic plasma brain membranes (SPM) and to lymphocyte, platelet and erythrocyte membranes. In the synaptic plasma membranes, more demethylated than methylated dibenzazepine derivatives were bound and the binding affinity was decreased. By contrast, in lymphocyte and platelet membranes more methylated derivatives were bound. Phosphatidylserine (PS) enhanced significantly the binding of methylated TCA in SPM without changing the dissociation constant (Kd). Lysophosphatidylserine did not affect the binding. PS also caused an increase of 3H-imipramine binding to lymphocyte membranes but the binding to platelet membranes was not affected. PS also enhanced 3H-5-HT uptake into platelets and 3H-noradrenaline uptake into lymphocytes.

Alpha-adrenolytic properties of apogalanthamine and azapetine analogs.

Selectivities were examined between alpha 1 and alpha 2-adrenolytic activities of two apogalanthamine analogs (dibenzazocine derivatives), 6-methyl-5,6,7,8-tetrahydrodibenz[c,e]-azocine (DA-VIII-Me) and its N-allyl analog (DA-VIII-allyl), and two dibenzazepine derivatives, azapetine (DA-VII-allyl) and its N-methyl analog (DA-VII-Me). The alpha-adrenolytic activities were evaluated as inhibitory effects against the response to norepinephrine of isolated vas deferens and anococcygeus muscle of rats. The pA2 values for DA-VIII-Me, DA-VIII-allyl, DA-VII-Me and azapetine on the isolated rat vas deferens were 7.32, 7.76. 6.61 and 7.78 respectively, which were similar to those on the anococcygeus muscle. The alpha 2-adrenolytic activities of these compounds against the twitch-inhibitory response to clonidine in transmurally stimulated rat vas deferens and guinea-pig ileum were less potent than those against the above alpha 1-adrenoceptors. In addition, their inhibitory activities on the aggregation of human platelets induced by norepinephrine were weaker than those of phentolamine and yohimbine. These results indicate that the apogalanthamine and azapetine analogs tested are more selective in blocking alpha 1-adrenoceptors than alpha 2-adrenoceptors.

Evaluation of the cytotoxicity of tricyclic antidepressants in primary cultures of rat hepatocytes

Primary cultures of hepatocytes from postnatal Sprague-Dawley rats were grown in arginine-deficient, ornithine-supplemented medium to inhibit fibroblastic overgrowth and to selectively isolate relatively pure cultures of parenchymal hepatocytes. This system of primary cultures of rat hepatocytes was utilized to evaluate the cytotoxicity of certain tricyclic antidepressant drugs (TCAs). The compounds tested were chosen to represent two distinct chemical classifications of TCAs: the dibenzazepine derivatives, imipramine (1) and desipramine (D), and the dibenzocycloheptadiene derivatives, amitriptyline (A) and nortriptyline (N). The study also allowed direct comparison of the parent tertiary amines, A and I, and their respective demethylated pharmacologically active metabolites, N and D. The hepatotoxicity of the compounds was determined by measuring leakage of cytoplasmic enzymes, lactate dehydrogenase (LDH) and glutamic-pyruvic transaminase (GPT), into the culture medium and by assessing cell viability by the trypan blue dye exclusion test. LDH leakage was a more sensitive index of early cellular injury in this study. The compounds demonstrated a dose- and time-dependent order of toxicity; their hepatotoxicity potency was ranked as A = N greater than D greater than I.

Synthesis of 11-phenyl-5,6-dihydro-11H -dibenz(b,e)azepine Derivatives

Synthesis of 11-phenyl-5,6-dihydro-11H -dibenz(b,e)azepine Derivatives

Equal inhibitory effect of dimethyl- and monomethyl-β-aminopropionylic derivatives of dibenzazepine on the uptake of [ 3H]noradrenaline by rat brain synaptosomes

Equal inhibitory effect of dimethyl- and monomethyl-β-aminopropionylic derivatives of dibenzazepine on the uptake of [ 3H]noradrenaline by rat brain synaptosomes

Inhibition of cellular ATP-hydrolyzing activity by tricyclic antidepressants and phenothiazine tranquilizers

In a variety of cellular and subcellular preparations, total ATP-hydrolyzing activity was potently inhibited by tricyclic antidepressants (TA) and phenothiazine tranquilizers (PT). In leukocytes, preincubation of the cells with 5 × 10 −4 M TA and 1 x 10 −4 M PT resulted in up to 87% and 94% inhibition of the ATPase activity. Among TA, dibenzocycloheptadienes were somewhat more potent inhibitors than were derivatives of dibenzazepine. Substitution, at the position 2 of the phenothiazine nucleus, by a halogen and particularly by the CF 3 group, increased the inhibitory strength of PT. However, most effective in inhibiting ATPase was thioridazine, structurally differing from mesoridazine, the weakest inhibitor in this study, by a methylmercapto group instead of a methylsulfinyl substituent. The inhibition by the drugs was markedly reduced in the presence of millimolar ATP. The results indicate a possible adverse effect of these drugs on the cellular energy-yielding capacity.

Binding of drugs to human serum albumin—I. circular dichroism studies on the binding of some analgesics, sedatives and antidepressive agents

The possibility of using circular dichroism measurements as a method for studying drug-protein binding has been investigated with 52 analgesics, sedatives and antidepressive agents. The binding to human serum albumin (HSA) in 0·1 M KCl at pH 7.4 and 25–27° has been studied. New extrinsic Cotton effects have been obtained from HSA-complexes with 24 different drugs. Of the drugs known to form strong complexes with HSA, only p-acetanilides and acetylsalicylic acid failed to give extrinsic Cotton effects with HSA at the experimental conditions used. The structural requirement for binding of the drugs to HSA and the possibilities for studying the binding sites of HSA are discussed. In some cases (e.g. the benzdiazepine and dibenzazepine derivatives) a plane ring system with high electron density seems to be an essential factor for strong binding capacity.

Thymoleptics on avoidance conditioning in guinea pigs

The activity on avoidance behavior of four thymoleptics has been investigated in guinea pigs. The dibenzocycloheptadiene derivatives depress avoidance responses much more than dibenzazepine derivatives. The results are discussed especially in connection to the species sensitivity and to the tranquilizing properties of these thymoleptics.