STRUCTURE AND ACTIVITY RELATIONSHIP OF MONOAMINE OXIDASE INHIBITORS, PHENYLACETYLHYDRAZIDE DERIVATIVES

Abstract

The inhibitory effect of 14 derivatives of phenylacetylhydrazide on MAO were examined using rat brain and liver enzyme preparations in vitro and in vivo. N-benzyl-N[image]-phenylacetylhydrazide (P-5307) was the most active MAO inhibitor among the derivatives assayed. MAO-inhibition and central nervous system effects of P-5307 were comparatively investigated using iproniazid and 1-methyl-2-phenethylhydrazine (JB-516) as controls. The introduction of any aliphatic and aromatic groups into 1 H at the terminal amino N of the phenylacetylhydrazide molecule increased the inhibitory activity. Substitutions of 1 or 2 hydrogen at a-position of the molecule with an aliphatic or aromatic group decreased the activity. N-phenethyl-N[image]-phenylacetylhydrazide (P-5305) and N-isopropyl-N[image]-phenylacetylhydrazide (P-5613) were as active as iproniazid, while P-5307 was more active than iproniazid. P-5307 and iproniazid suppressed MAO activity of liver and brain mitochondria more than that of both original homogenates, whereas, JB-516 inhibited the MAO of the homogenates and mitochondria of brain and liver in the same degree. P-5307 and iproniazid were more active on liver than on brain MAO. No such difference in the sensitivity was observed in JB-516. The duration of inhibitory effect of P-5307, iproniazid and JB-516 on brain MAO in vivo was longer than that on liver MAO. Subacute administration of P-5307, iproniazid and JB-516 to rats increased the brain norepinephrine. Rats which received iproniazid showed a piloerection and motor excitement, though the increase in cerebral norepinephrine was the lowest. No appreciable effects of P-5307, iproniazid and JB-516 were observed on mice performance of forced motor activity using the rotating cylinder. The spontaneous motor activity of mice in the photocell cage was not affected by P-5307 and iproniazid, but was markedly increased by JB-516. The pretreatment of P-5307, iproniazid and JB-516 did not induce sleep in mice receiving nonanesthetic dose of methylhexabital. However, the sleep induced by anesthetic dose of the barbiturate was prolonged by iproniazid and JB-516 but not by P-5307. The tonic extensor reflexes in mice produced by electroshock or Metrazol (pentylenetetrazole) were not significantly suppressed by P-5307, iproniazid and JB-516. The acute toxicity studies excluded the correlation between the toxicity and inhibitory effect on MAO. P-5307 proved the lowest toxicity in rats and mice. The subacute toxicity studies excluded a damaging effect of P-5307 on the tissues such as liver, kidney and testis in rats. Iproniazid and JB-516 caused a slight cloudy swelling and cell infiltration in the Glisson''s sheath in liver.