Recent Advances in GABA Agonists, Antagonists and Uptake Inhibitors: Structure–Activity Relationships and Therapeutic Potential

Differential effects of GABA A and GABA B agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice

“…The role of GABA B receptors in behavioral sensitization to ethanol is of particular interest, given reports that baclofen is effective in preventing the development of behavioral sensitization to drugs such as the mu agonist DAGO and cocaine (Kalivas and Stewart 1991). Thus, the present experiments examined the ability of THIP and baclofen, selective GABA A and GABA B agonists, respectively (Hill and Bowery 1981;Krogsgaard-Larsen et al 1988), to prevent development of sensitization to ethanol. DBA/2 J mice were selected for study, due to the robust sensitization that occurs in these mice.…”

GABA agonists and antagonists

“…2), for GABA interaction with different types of GABA,-receptor is not trivial, since GABA dysfunction is obviously linked to a wide range of neurological and psychiatric conditions, and agents with a specificity for these subtypes may well have considerable therapeutic interest. 38 In particular, it is likely that definite distinctions will eventually be made between postsynaptic and presynaptic GABA,-receptors, with autoreceptors forming a separate group. A major caveat in all such studies is the possibility that the observed activity of particular ligands may in fact be greatly influenced by uptake mechan i s m~.~~ This is especially so if the agents themselves are inhibitors of this process, when their apparent activity is likely to be confounded by accumulation of endogenous GABA in the region of the receptors at GABAergic synapses.…”

“…Nevertheless, the (S)-isomer of the 4-Me derivative has been used for this purpose. 38 Alteration of the basic function in such unsaturated analogs, as in 2-3-(amidinothio)-propenoic acid (ZAPA) provides extremely potent agonist activity at low-affinity GABAA sites60; unfortunately, such S-thioureyl analogs are inherently unstable due to ready oxidation, which severely limits their use. From the structure-action point of view, however, ZAPA is again of considerable interest since the double bond restricts the available configurations that it can assume, emphasizing the preference for an extended form, while the corresponding E-analog is inactive.…”

Structural features of muscimol, a potent GABAA receptor agonist, crystal structure and quantum chemicalab initio calculations

“…This objective was fulfilled by the synthesis of 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP) [ 18], and this bicyclic muscimol analogue and its equally potent and specific amino acid analogue isoguvacine [19] ( Fig. 1) became standard GABA A receptor agonists [6,10,20]. Like muscimol, THIP is capable of penetrating the BBB, and THIP has been studied in a variety of clinical conditions (for reviews, see refs.…”