A number of companies have tried to develop selective GABA-A drugs that are agonists only at the GABA-A subunits thought primarily related to anxiolysis (a2 and a3) while dropping out activity at other subunits associated with sedation or ataxia. Good idea, hard to execute. Pfizer/Neurogen had three selective compounds fail due to poor efficacy, NeuroSearch had one that demised due to mild allergic reactions (interestingly, at higher GABA concentrations, it became an antagonist at an unknown receptor site), and Pfizer/Indevus' pagoclone also ran into efficacy concerns, though Pfizer's last batch of trials were strangely set up--and the receptor subtype profile was never identified. Thus in mice, it seems that being selective for alpha2 and alpha3 works very well, the mice are quite relaxed, mentally sharp, good dancers. But being that selective in humans tends to drop efficacy as well. This is just a guess about the Merck drug, they havent called me yet to discuss the failure in detail.....
Harry Tracy
NeuroInvestment |
