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.

Abstract

The antagonist effect of (±)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (+)-HA-966 were resolved, the (R)-

The Family of Na+/Cl− Neurotransmitter Transporters

“…There is evidence suggesting that the glycine site on NMDA receptors is not saturated (Wood and Sidhu, 1986). The modulatory role of the glycine site makes it an attractive target for therapeutic anticonvulsant and neuroproteetive agents (Priestley et al, 1990;Singh et a!., 1990). It is apparent that modulating the activity of the glycine transporters in the vicinity of the NMDA receptor may achieve similar pharmacological effects with less side effects than the use of agonists and antagonists that interact with the glycine site in the NMDA receptor.…”

Enhanced Vascular Neuronal Nitric-Oxide Synthase-Derived Nitric-Oxide Production Underlies the Pressor Response Caused by PeripheralN-Methyl-d-Aspartate Receptor Activation in Conscious Rats

“…It is noteworthy that consistent with a previously reported study (Adam et al, 2001) the selected dose of R-(ϩ)-HA-966 produced no change in basal BP. It is possible that R-(ϩ)-HA-966's inability to fully abrogate the NMDA-evoked pressor response, as did AP-5, could be caused by its partial blockade of the NMDAR by targeting the glycine modulatory site (Foster and Kemp, 1989;Singh et al, 1990) or because we used a relatively low dose of the drug. It is noteworthy that higher R-(ϩ)-HA-966 doses were not attempted because they are associated with central (behavioral) effects (McMillen et al, 2004).…”

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).…”

“…In the chloral hydrate anesthetized rat, both drugs are capable of reversibly suppressing impulse flow leading to a compensatory increase in DA levels in terminal field areas, including the dorsal and ventral striatum (Gessa et al 1966;Hillen and Noach 1971;Roth et al 1973;Shepard and Lehmann 1992). S(-)HA-966 is considerably more potent in this regard than either GHB or the R( ϩ ) enantiomer of HA-966, which also exhibits affinity for the glycine allosteric site on the N-methyl-D-aspartate (NMDA) receptor (Singh et al 1990). The inhibitory effects produced by lower doses of GHB ( р 200 mg/kg) and S(-)HA-966 ( р 10 mg/kg) are accompanied by a complete cessation of bursting activity and the emergence of a pacemaker-like firing pattern that is not typically observed in vivo (Engberg and Nissbrandt 1993;Shepard et al 1995).…”