1‐Hydroxy‐3‐amino‐pyrrolidone‐2 (HA‐966): a new GABA‐like compound, with potential use in extrapyramidal diseases

Abstract

Summary1. The drug HA-966 (1-hydroxy-3-amino-pyrrolidone-2), which chemically resembles the cyclic form of GABA, has been studied for neuro-pharmacological properties and for effects on the catecholamine content of the corpus striatum. 2. The acute effects on spontaneous behaviour of rodents included flaccid catalepsy and reversible tranquillization in doses which were 5% or less of the lethal dose. Long lasting depression of the CNS, followed by complete recovery, was produced in the cat and the dog. In the monkey HA-966 caused periodical sleeping episodes. 3. The exploratory behaviour and the amphetamine-induced motor activity in mice were blocked by HA-966. The toxicity of amphetamine in aggregated mice was only moderately reduced, suggesting that HA-966 differs from neuroleptics. 4. Tremors induced by chemical agents (nicotine, zinc and tremorine) were markedly inhibited by HA-966. The muscarinic effects of tremorine were not reduced by HA-966, indicating a selective central antitremor effect. 5. HA-966 elevated the threshold to strychnine convulsions and abolished the ipsilateral flexor reflex, while not having motor endplate blocking properties. It is suggested that HA-966 depresses central internuncial neurones. 6. In rats and rabbits HA-966 produced synchronous EEG and inhibited the sensory arousal in doses not causing sedation. In the monkey the drug caused a periodical dissociation between 'sleep-EEG' and behaviour. 7. In rat brain, HA-966 selectively elevated the dopamine content in the corpus striatum, while no changes in noradrenaline and 5-hydroxytryptamine contents could be demonstrated. The effect was still present when dopa synthesis was inhibited with a-methyl-p-tyrosine. 8. Several effects of intravenously administered HA-966 became manifest after an appreciable delay and in hepatectomized mice the effects were much reduced. It is postulated that HA-966 is converted to a pharmacologically active metabolite.HA -966, drug for extrapyramidal diseases 9. The results are discussed in the light of current views on drug therapy in extrapyramidal conditions and a GABA-related hypothesis as to the mode of action of HA-966 is presented.

The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate

“…It is therefore relevant that although HA-966 appears from the results of Biscoe etal. (1978) to be a less potent and selective NMA-antagonist than reported here for ketamine, it does cross the blood barrier and induces behavioural, neurophysiological and EEG changes (Bonta, DeVos, Grijsen, Hilden, Noach & Sim, 1971) not dissimilar to those reported for the dissociative anaesthetics (Domino, 1964).…”

Pertussis Toxin Lesions of the Rat Substantia Nigra Block the Inhibitory Effects of the γ-Hydroxybutyrate Agent, S(-)HA-966 without Affecting the Basal Firing Properties of Dopamine Neurons

“…Not surprisingly, HA-966 and GHB share nearly identical neurochemical, electrophysiological, and behavioral profiles (Bonta et al 1971;Singh et al 1990;Waldmeier 1991;Engberg and Nissbrandt 1993;Shepard et al 1995). Both compounds have sedative, anxiolytic, and antispasmotic properties, although neither is in widespread clinical use in the United States because of their ability to induce EEG changes in animals similar to those observed in human absence epilepsy (Bonta et al 1971;Snead,1988).…”

“…Not surprisingly, HA-966 and GHB share nearly identical neurochemical, electrophysiological, and behavioral profiles (Bonta et al 1971;Singh et al 1990;Waldmeier 1991;Engberg and Nissbrandt 1993;Shepard et al 1995). Both compounds have sedative, anxiolytic, and antispasmotic properties, although neither is in widespread clinical use in the United States because of their ability to induce EEG changes in animals similar to those observed in human absence epilepsy (Bonta et al 1971;Snead,1988). However, recent clinical data showing that GHB is effective in suppressing alcohol and opiate withdrawal (Gallimberti et al 1992(Gallimberti et al , 1993 and that S(-)HA-966 can prevent cocaine sensitization in rats (Morrow et al 1997) and attenuate PCP-induced changes in dopamine (DA) metabolism in the primate prefrontal cortex (Jentsch et al 1997) has rekindled in-terest in the potential therapeutic applications of these compounds.…”

Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative.

“…However, unlike 7-chlorokynurenic acid, which may be a full antagonist (15), HA-966 appears to be a low-efficacy partial agonist at the glycine site (12)(13)(14). HA-966 has been shown previously to possess anticonvulsant, anti-tremor, and sedative actions in rodents and causes a marked elevation of dopamine concentration in the striatum (16,22). Since it is a racemic compound, we recently have resolved HA-966 (18) and now present evidence that glycine/NMDA receptor antagonism and anticonvulsant activity resides in the (R)-(+)-enantiomer.…”