Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-Thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators

Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 3: Identification and biological activity of indanone containing mGlu2 receptor potentiators

“…Potency also decreased with a phenyl group (18). Interestingly when two larger groups, for example, a butyl group and a cyclopentyl group (19) are present, activity is 5-fold less indicating a limit to the steric bulk that can be accommodated at the binding site.…”

“…For example, a simple carboxylic acid (22), an imide (23) and an acyl sulfonamide (24) showed activity close to the tetrazole. Due to our previous success in a related series of compounds 18 replacing the tetrazole with a thiopyridine moiety, we investigated incorporating this group. Gratifyingly, this strategy gave a compound (25) that was close in potency to the original lead.…”

Drugs in the tetrazole series. (Review)

“…The class of selective potentiators of metabotropic glutamate receptor includes compound 7, studied by the authors of [22,23]. In this case the tetrazole ring turned out to be not the most successful functional group.…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…It is noteworthy that one compound, a benzotriazole analog (compound VIII, Table 8), also enhanced mGlu3 receptor activity with a potency only a 5-fold weaker than that at the mGlu2 receptor. Moreover, replacement of the phenyltetrazol by a thiopyridyl or a phenylpropanoic acid end group resulted in compounds with improved brain penetration (Pinkerton et al, 2004a;Cube et al, 2005). Another lead structure emerging from this HTS was a phenyltetrazolindanone (rather than -acetophenone) compound .…”