Novel-Type GABA PAMs: Structure-Activity Relationship in Light of the Protein Structure.

Selecting a known HTS hit with the pyrazolo[1,5-]pyrimidine core, our project was started from CMPPE, and its optimization was driven by a ligand-based pharmacophore model developed on the basis of published GABA positive allosteric modulators (PAMs). Our primary goal was to improve the potency by finding new enthalpic interactions. Therefore, we included the lipophilic ligand efficiency (LLE or LipE) as an objective function in the optimization that led to a carboxylic acid derivative ().

6-Aryl-quinazolines as novel GABA receptor positive allosteric modulators.

The systemic use of GABA orthosteric agonist baclofen might be limited due to its detrimental properties: sedation and motor impairment. In contrast, GABA positive allosteric modulators produce less adverse effects. Using BHF-177 as a starting point, we found a new active scaffold: the 6-aryl-quinazoline scaffold.