Monoamine oxidase inhibition by novel antidepressant tetrindole.

The novel antidepressant tetrindole (2,3,3a,4,5,6-hexahydro-8-cyclohexyl-1H[3,2,1-j,k] carbazole) was found to be a selective inhibitor of monoamine oxidase A (MAO A). In vitro it inhibited rat brain mitochondrial MAO A in a competitive manner with Ki value of 0.4 microM. A 60 min preincubation did not change the competitive mode of interaction between enzyme and tetrindole (Ki value was 0.27 microM). The inhibition of rat brain mitochondrial MAO B was of mixed type with Ki value of 110 microM. Dilution or dialysis of mitochondrial suspension did not restore MAO A activity after inhibition by tetrindole both in vitro and in vivo, whereas inhibition of MAO B in vitro was completely reversible. Oral administration of tetrindole inhibited rat brain and liver mitochondrial MAO A by 80% within 0.5-1 hr and the onset of recovery of enzyme activity became evident after 24 hr. A small inhibition of MAO B (-20-30%) was observed in isolated brain and liver mitochondria within 1-6 hr and enzyme activity had completely recovered after 16 hr. The data obtained indicate that antidepressant activity of tetrindole may be explained by selective inhibition of MAO A, however an apparent discrepancy between competitive manner of MAO A inhibition in vitro and poor recovery of enzyme activity in vivo does not allow us to decide whether tetrindole is a "tight-binding" reversible inhibitor or a selective irreversible inhibitor of MAO A.

Modification of the activity of mitochondrial monoamine oxidases in vitro and in vivo.

Treatment of bovine brain mitochondrial membranes with iproniazid (Ip) (1 mM, 15 min) inhibited monoamine oxidase (MAO) activity (substrates: 5-hydroxytryptamine, tyramine, dopamine) and significantly (about 7-fold) increased histamine deaminating activity (HDA). A selective inhibitor of MAO-A clorgyline (contrary to deprenyl) prevented the increase in HDA. Ip (200 mg/kg; within 10-16 h after parenteral administration) markedly (about 6-fold) increased the level of the HDA) in brain mitochondria of mice and guinea pigs. At the same time, a decrease in content of histamine (Hi) and increase in content of 5-hydroxytryptamine was noted in the brains of mice. In anesthetized and non-anesthetized guinea pigs Ip decreased (or prevented) the bronchoconstriction and toxic effects caused by Hi. The antihistamine effects of Ip are apparently due to its being able to induce reversible qualitative alteration (transformation) of the catalytic activity of the membrane-bound MAO of type A, which acquires as a result of this transformation potent HDA.

Pharmacological properties of 2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino [3,2,1-j,k]carbazol hydrochloride (pirlindole), a new antidepressant.

The hydrochloride salt of 2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazol hydrochloride (pirlindole) exerts pharmacological effects typical of antidepressants. This compound antagonizes the depressant effects of reserpine and tetrabenazine and potentiates the central effects of amphetamine and l-dopa. It also enhances the head-twitch effect of 5-hydroxy-tryptophan, the effects of noradrenaline, adrenaline, serotonin, tyramine on blood pressure as well as the hypertensive and tremor activities of tryptamine. Pirlindole inhibits the neuronal uptake of noradrenaline and exerts reversible, short-lasting anti-MAO activity. It does not possess anti-cholinergic activity. Clinical trials have shown pirlindole to be effective as an antidepressive drug.

Pyrazidol, a new drug with antidepressant properties.

During the search for new psychotropic drugs, a group of pyrazinoindole derivatives have been synthetized at the All Union Chemical Pharmaceutical Research Institute. Especially effective and having antidepressant activities is the hydrochloride of 1,10-trimethylene-8-methyl-1,2,3,4-tetrahydropyrazino (1,2-a) indole, named pyrazidol. Pyrazidol differs from any already known antidepressant for its chemical structure, the general pattern of activity and its neurochemical mechanism of action. The drug combines an inhibiting action on the neuronal uptake of monoamines with a monoamineoxidase inhibiting activity. As MAO-inhibitor, pyrazidol mainly impairs serotonin deamination, and acts only slightly on tyramine deamination. Furthermore, the anti-MAO action of pyrazidol is of short duration. Then, pyrazidol constitutes a drug with a particular profile of therapeutic activity.