A new class of N,N-diethyl-(2-arylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides (3f-y),
as azaisosters of Alpidem, was prepared following a novel synthetic method and their
affinities for both the peripheral (PBR) and the central (CBR) benzodiazepine receptors
were evaluated. Binding assays were carried out using both [3H]PK 11195 and [3H]Ro
5-4864 as radioligands for PBR, whereas [3H]Ro 15-1788 was used for CBR, in rat kidney
and rat cortex, respectively. The tested compounds exhibited a broad range of binding
affinities from as low as 0.76 nM to inactivity and most of them proved to be high
selective ligands for PBR. The preliminary SAR studies suggested some of the structural
features required for high affinity and selectivity; particularly the substituents
on the pyrimidine moiety seemed to play an important role in PBR versus CBR selectivity.
A subset of the highest affinity compounds was also tested for their ability to stimulate
steroid biosynthesis in C6 glioma rat cells and some of these were found to increase
pregnenolone formation with potency similar to Ro 5-4864 and PK 11195.