piperidines and cimoxatone

The clinically tested reversible inhibitors of monoamine oxidase A (RIMAs) include brofaromine, moclobemide and toloxatone. Moclobemide has shown unequivocal antidepressant activity against serious depressive illness in 4 placebo-controlled double-blind trials. It has been compared with amitriptyline, imipramine, clomipramine, desipramine, maprotiline, fluoxetine, fluvoxamine, tranylcypromine, toloxatone, mianserin and amineptine in the treatment of depressive disorders. Meta-analysis showed convincing evidence of moclobemide efficacy, comparable with the most potent antidepressants available. The efficacy of moclobemide has been demonstrated in psychotic and non-psychotic depression, in depression with and without melancholia, in endogenous depression (both unipolar and bipolar), in retarded depression and in agitated depression. The efficacy of moclobemide, allied to the unusually benign side effect profile, has led to exploration of its use in other disorders. Two small studies have given encouraging results in the treatment of attention-deficit hyperactivity disorder. Large placebo-controlled studies have shown the activity of moclobemide in the depression that accompanies dementia (such as senile dementia of Alzheimer type). The results also suggested that, in this patient population, cognitive ability improved in parallel. Social phobia has also been shown to improve on treatment with either moclobemide or brofaromine. Clinical trials are in progress on the effect of moclobemide in chronic fatigue syndrome. Moreover, there are encouraging results with the use of brofaromine and moclobemide in panic disorder. Other disorders in which treatment with RIMA is of interest include agoraphobia, bulimia, borderline personality disorder, post-traumatic stress disorder, compulsive hair pulling (trichotillomania), dysmorphophobia, kleptomania as well as various anxiety syndromes.

Topics: Alzheimer Disease; Antidepressive Agents, Tricyclic; Attention Deficit Disorder with Hyperactivity; Benzamides; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Panic Disorder; Phobic Disorders; Piperidines

Subcutaneous injection of 1 mg/kg 5-hydroxytryptamine (5-HT) reduced the intake of a 10% sucrose solution in rats. A single injection of the monoamine oxidase inhibitor (MAOI) clorgyline enhanced the anorectic effect of 5-HT. Such an effect persists 2, 24, 48, 72 and 96 h after injection. The clorgyline treatment almost completely inhibited type A MAO activity in the liver at 2 h post-injection. By 120 h, the time at which potentiation of 5-HT induced anorexia disappeared, MAO-A activity had returned to 80% of control values. These results demonstrate that the clorgyline effect is long-lasting and irreversible. Brofaromine (5 mg/kg) and cimoxatone (20 mg/kg) also enhanced the anorectic effect of 5-HT injected 2 h later. The potentiating effects of brofaromine and cimoxatone were not observed when 5-HT was administered 24 h later. These results indicate that brofaromine and cimoxatone are short-acting, reversible inhibitors of MAO-A activity in vivo. Moclobemide (30 mg/kg) failed to enhance the anorectic action of 5-HT injected 2 and 24 h later. The potentiation of 5-HT induced anorexia may be a useful behavioural test for investigating the degree of reversibility, and time course of action of MAOIs.

Topics: Animals; Benzamides; Clorgyline; Drug Synergism; Feeding Behavior; Male; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Piperidines; Rats; Rats, Inbred Strains; Serotonin

Intraperitoneal injection of cimoxatone, moclobemide, amiflamine CGP 11305 A (all 5 mg/kg) increased pressor responses to intravenous tyramine (100 micrograms) in conscious, freely moving rats. Area under mean arterial pressure curve increased by 7.01, 4.28, 5.3 and 3.46 fold respectively. Clorgyline (2 mg/kg) increased area under pressor response curve by 10.4 fold. Tyramine responses returned to normal 24 hours after reversible inhibitors but were still potentiated 24 hours after clorgyline.

Topics: Animals; Benzamides; Blood Pressure; Clorgyline; Drug Synergism; Male; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Phenethylamines; Piperidines; Rats; Rats, Inbred Strains; Tyramine

The aim of this study was to assess a) the validity of an ex vivo approach for the estimation of the in vivo MAO A inhibitory properties of the new short-acting MAO A inhibitors, amiflamine, brofaremine, cimoxatone and moclobemide, by studying the effect of dilution of brain and liver homogenates from pretreated rats on the degree of enzyme inhibition; b) the displaceability of the inhibitors from the enzyme by substrate in brain and liver homogenates from pretreated rats; c) idem, in the in vivo situation in the brain, by increasing the availability of the substrate by releasing it from its endogenous stores by tetrabenazine. The following results were obtained: The ex vivo approach was found to be valid for moclobemide in brain and liver and for cimoxatone in brain tissue; a slight underestimation of the MAO A inhibitory effect of the latter in the liver is likely. Definite underestimation occurred with amiflamine in both tissues. Kinetic investigations using homogenates from pretreated rats showed amiflamine to be a competitive inhibitor; cimoxatone was competitive in the liver but showed a more complex pattern in the brain. Moclobemide was noncompetitive in both tissues, as has been shown previously for brofaremine. Moclobemide prevented the deamination of dopamine and serotonin released from their striatal stores by tetrabenazine nearly as efficiently as clorgyline at an otherwise equieffective dose; cimoxatone was somewhat less effective relative to the reference compound, as was brofaremine, which was however given at a more effective dose. Amiflamine was much less effective than clorgyline at protecting dopamine, but equieffective with respect to serotonin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benzamides; Brain; Clorgyline; Dopamine; Female; Homovanillic Acid; Kinetics; Liver; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Phenethylamines; Piperidines; Rats; Rats, Inbred Strains; Serotonin