The novel neuropsychotropic agent milacemide is a specific enzyme-activated inhibitor of brain monoamine oxidase B.

The novel neuropsychotropic agent milacemide hydrochloride (2-n-pentylaminoacetamide HCl) is a highly selective substrate of the B form of monoamine oxidase (EC 1.4.3.4; MAO). Under the in vitro conditions used in the present study, milacemide acts as an enzyme-activated, partially reversible inhibitor of MAO-B. A reversible inhibition of MAO-A activity is also observed at high concentrations. The inhibitory activity of milacemide is significantly greater for MAO-B. In vivo, after single or repeated oral administration, a specific inhibition of MAO-B is apparent in brain and liver, with a lack of inhibition of the MAO-A activity. In contrast to the irreversible inhibitory action of L-deprenyl, the recovery of MAO-B activity in vivo after milacemide administration is significantly faster, a result suggesting that it is a partially reversible inhibitor. The selective inhibitory effect of milacemide for MAO-B in vivo is confirmed by its potentiation of phenylethylamine-induced stereotyped behavior, whereas vasopressor responses to tyramine were not affected. These observations suggest that milacemide could enhance dopaminergic activity in the brain and could be used as therapy for Parkinson's disease in association with L-3,4-dihydroxyphenylalanine.

Formation of the neurotransmitter glycine from the anticonvulsant milacemide is mediated by brain monoamine oxidase B.

Milacemide (2-n-pentylaminoacetamide) is a secondary monoamine that in the brain is converted to glycinamide and glycine. This oxidative reaction was suspected to involve the reaction of monoamine oxidase (MAO). Using mitochondrial preparations from tissues that contain MAO-A and -B (rat brain and liver), MAO-A (human placenta), and MAO-B (human platelet and bovine adrenal chromaffin cell), it has been established that mitochondria containing MAO-B rather than MAO-A oxidize (H2O2 production and glycinamide formation) milacemide. The apparent Km (30-90 microM) for milacemide oxidation by mitochondrial MAO-B preparations is significantly lower than that for milacemide oxidation by mitochondrial MAO-A (approximately 1,300 microM). In vitro MAO-B (l-deprenyl and AGN 1135) rather than MAO-A (clorgyline) selectively inhibited the oxidation of milacemide. These in vitro data are matched by ex vivo experiments where milacemide oxidation was compared to oxidation of serotonin (MAO-A) and beta-phenylethylamine (MAO-B) by brain mitochondria prepared from rats pretreated with clorgyline (0.5-10 mg/kg) and l-deprenyl (0.5-10 mg/kg). Furthermore, in vivo experiment demonstrated that l-deprenyl selectively increased the urinary excretion of [14C]milacemide and the total radioactivity with a concomitant decrease of [14C]glycinamide. Such changes were not observed after clorgyline treatment, but were evident only at doses beyond clorgyline selectivity. The present data therefore demonstrate that milacemide is a substrate for brain MAO-B, and its conversion to glycinamide, further transformed to the inhibitory neurotransmitter, glycine, mediated by this enzyme may contribute to its pharmacological activities.

Piracetam facilitates retrieval but does not impair extinction of bar-pressing in rats.

Rats were trained on a continuously reinforced bar-press response for water reward. Seven days later they were retested for retention, with or without pretest injection of the nootropic drug, piracetam. Drug-treated animals had significantly shorter response latencies than saline-treated animals. The results are interpreted as a facilitation of retrieval processes after forgetting. The experiment was extended under extinction conditions and it was found that after three sessions there was a tendency to facilitate extinction when response latency is used as the extinction index. The clinical interest of a drug which facilitates the retrieval aspect of the memory process without impairing extinction is discussed.

Passive avoidance behavior in rats after electroconvulsive shock: facilitative effect of response retardation.

Rats were trained in a one-trial passive avoidance task and then were submitted to electroconvulsive shock (ECS) or to sham ECS. Twenty-four hours later they were tested for retention, with the door opened either immediately or 30 sec after the beginning of the test. Rats initially forced to avoid for 30 sec continued to avoid for the entire test, but the others had the usual low step-through latencies seen with ECS-treated animals. Activity measures for those animals stepping through differentiated groups having received footshock from those not having footshock and ECS. A retest 5--10 min later showed "recovery" in the amnestic animals and continued avoidance behavior for those that avoided on the first test. Results are taken as evidence that ECS effects are not on memory storage but on the capacity of the animal to organize information effectively and quickly in order to produce an adaptive response.