This chapter presents new clinical applications of the prototypic
GABA(B) receptor agonist baclofen for the treatment of addiction by drugs of abuse, such as alcohol,
cocaine,
nicotine,
morphine, and
heroin, a novel
baclofen prodrug Arbaclofen placarbil, the
GABA(B) receptor agonist AZD3355 (Lesogabaran) currently in Phase 2 clinical trials for the treatment of
gastroesophageal reflux disease, and four positive allosteric modulators of
GABA(B) receptors (
CGP7930,
GS39783, NVP-
BHF177, and BHFF), which have less propensity for the development of tolerance due to receptor desensitization than classical
GABA(B) receptor agonists. All four compounds showed
anxiolytic affects. In the presence of positive allosteric modulators the "classical"
GABA(B) receptor antagonists CGP35348 and
2-hydroxy-saclofen showed properties of partial
GABA(B) receptor agonists. Seven micromolar affinity
GABA(B) receptor antagonists,
phaclofen; 2-hydroxy-
saclofen; CGP's 35348, 36742, 46381, 51176; and SCH50911, are discussed.
CGP36742 (
SGS742) showed statistically significant improvements of working memory and attention in a Phase 2 clinical trial in mild, but not in moderate Alzheimer patients. Eight nanomolar affinity
GABA(B) receptor antagonists are presented (CGP's 52432, 54626, 55845, 56433, 56999, 61334, 62349, and 63360) that were used by pharmacologists for numerous in vitro and in vivo investigations. CGP's 36742, 51176, 55845, and 56433 showed
antidepressant effects. Several compounds are also available as radioligands, such as [(3)H]CGP27492, [(3)H]CGP54626, [(3)H]CGP5699, and [(3)H]CGP62349. Three novel fluorescent and three
GABA(B) receptor antagonists with very high specific radioactivity (>2,000 Ci/mmol) are presented. [(125)I]
CGP64213 and the photoaffinity
ligand [(125)I]
CGP71872 allowed the identification of
GABA(B1a) and
GABA(B1b) receptors in the expression cloning work.