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7-(Aminoacyl) and 7-(aminoalkyl) derivatives of 1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepines as potential antidepressant agents.

The synthesis of 7-(aminoacyl) and 7-(aminoalkyl) derivatives of 1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepines is described. These compounds were evaluated for antidepressant activity by their ability to inhibit tetrabenazine-induced ptosis in mice. Many compounds were found to be active in this animal model, and structure-activity relationships are discussed. Two analogues in particular, one from the 7-(aminoacyl) series (13) and one from the 7-(aminoalkyl) series (26), were of comparable potency to the antidepressant drugs desipramine and amitriptyline.

Animals↗

[Novel comparative profile of the clinical activity of antidepressive agents].

In order to develop practical criteria to guide in the selection of antidepressant medication according to depressive symptomatology, we propose a graphical representation of the clinical activity of 24 antidepressants according to a "star" model. Six parameters have been evaluated from 0 to 5 in comparison to reference drugs (rated 5) by 11 independent "blind" psychiatrists expert in pharmacotherapy. Three parameters were used as measures of therapeutic activity: antidepressant, psychostimulant, and anxiolytic, with iproniazide 75 mg/d, metamphetamine 15 mg/d, and diazepam 20 mg/d as reference drugs respectively. Three additional parameters assessed the level of side-effects: anticholinergic, sedative, and hypotensive, with atropine 0.75 mg/d, phenobarbital 200 mg/d, and iproniazide 75 mg/d as reference drugs respectively. The defined dose represented the standard maintenance daily dose for depressive outpatients. Mean values for each parameter, rounded off to the closest number, were used for the graphical representation. Results showed an excellent agreement among evaluators for the clinical profile of classical tricyclic and MAOI antidepressants, but serious divergences for the more recent drugs (e.g., viloxazine and mianserine), possibly reflecting more atypical or more variable clinical profile of these compounds.

Antidepressive Agents↗

[Pressor response to the stimulation of peripheral sympathetic nerves and the posterior hypothalamus in the presence of tricyclic antidepressive agents and nomifensine in dogs].

Acute experiments documented the peripheric action of tricyclic antidepressives (imipramine, chlorimipramine and amitriptyline). They evoked a significant hypotensive action (P less than 0.02), baroreceptor blockade and higher intensity and duration of pressor responses to exogenous noradrenaline, electric stimulation of the sympathetic nerves of the spleen, posterior hypothalamus or the central extremity of vagus nerve. These effects could be produced by the inhibition of noradrenaline reuptake and are antagonized by noradrenergic blockade with phentolamine. Nomifensine does not change arterial pressure, but its analeptic effect is able to awake anesthetized dogs. The pressor noradrenergic response is greater than that obtained with tricyclic antidepressives. The potentiation showed by the injection of dopamine was similar to that produced by imipramine. Injected into the cerebral ventricles of the dog, it did not changed arterial pressure, but crossed the blood-brain barrier. High doses of tricyclic antidepressives and nomifensine evoked inhibitory effects on adrenergic responses.

Amitriptyline↗

[Delay in the effect of antidepressive agents: pharmacologic approach].

A paradox which is not resolved in the use of antidepressants (ATD) is that in pharmacological studies of animal models of depression and in neurochemical studies, the onset of activity of all drugs is extremely rapid, whereas in human clinical practice the onset is delayed (15 days). An attempt is made to explain this in 3 ways, involving the synapse, transduction mechanisms, and cognition. Analysis of the impact of all ATDs shows that we are confronted with slow adaptive processes which are correlated with the delay observed in clinical practice. The interest of such considerations is that they may give rise to alternative therapies which are able not only to accelerate response, but also to increase it.

Affect↗