GABA analogs

Fused isoxazoles (631) were prepared as GABA analogs (75MI41604) and some exhibited CNS depression effects (74JAP(K)7480062) or were effective as minor tranquilizers, muscle relaxants and/or sleep inducers (76USP3966748, 79USP4163057). 

Gabapentin, a non-benzodiazapine GABA analog, was modestly effective in a 14-week controlled trial in SAD. Most patients were titrated to a maximal dose of 3600 mg/day.58 Pregabalin 600 mg/day was effective for social anxiety, fear, and avoidance behavior in a 10-week controlled trial.63 Pregabalin was well tolerated, and the most common side effects were somnolence and dizziness. 

Winkler, M., Knall, A.C., Kulterer, M.R. and Klempier, N. (2007) Nitrilases catalyze key step to conformationally constrained GABA analogous y-amino acids in high optical purity. The Journal of Organic Chemistry, 72, 7423-7426. 

During the last two decades, a large number of GABA analogs based on A-substitutions of the GABA mimetics nipecotic acid, guvacine, THPO, THAO, and exo-THPO... 

Scheme 2.74 Rapid preparation of GABA analogs using a combination of immobilized enzymes and supported reagents.

The story of the discovery of pregabalin (2) began in 1991, when Silverman and Taylor published a paper on the anticonvulsant effect of 3-alkyl GABA analogs (Silverman et ah, 1991). Out of this collection of compounds, 3-isobutyl GABA stood out as the most active analog in the series, which protected mice from seizures induced by corneal electroshock. 

GABA analogs are used in the treatment of epilepsy and hypertension. Levels of GABA can also be increased by administering inhibitors of the GABA-degrading enzyme GABA aminotransferase. Another important neuro-transmitter, serotonin, is derived from tryptophan in a two-step pathway. 

Krogsgaard-Larsen, P. Hjeds, H. Curtis, D. R. Lodge, D. Johnston, G. A. R. Dihydromuscimol, thiomuscimol and related heterocyclic compounds as GABA analogs. 

Category Anticonvulsant GABA analog Half-life 6 hours... 

Gabapentin, a nonbenzodiazepine GABA analog, was effective for SAD in a 14-week placebo-controlled trial. The onset of effect occurred within 2 to 4 weeks. Patients reported dizziness and dry mouth. The effective dose of gabapentin ranged from 900 to 3600 mg daily given in three divided doses. ... 

---