Differential modulation of GABAA receptor function by aryl pyrazoles

Abstract Several aryl pyrazoles characterized by a different molecular structure (flexible vs constrained), but chemically related to rimonabant and AM251, were tested for their ability to modulate the function of recombinant α 1 β 2 γ 2L GABA A receptors expressed in Xenopus laevis oocytes. The effects of 6Bio-R, 14Bio-R, NESS 0327, GP1a and GP2a (0.3–30 μM) were evaluated using a two-electrode voltage-clamp technique. 6Bio-R and 14Bio-R potentiated GABA-evoked Cl − currents. NESS 0327, GP1a and GP2a did not affect the GABA A receptor function, but they acted as antagonists of 6Bio-R. Moreover, NESS 0327 inhibited the potentiation of the GABA A receptor function induced by rimonabant. The benzodiazepine site seems to participate in the action of these compounds. In fact, flumazenil antagonized the potentiation of the GABA A receptor induced by 6Bio-R, and NESS 0327 reduced the action of lorazepam and zolpidem. On the contrary, NESS 0327 did not antagonize the action of “classic” GABAergic modulators (propanol, anesthetics, barbiturates or steroids). In α 1 β 2 receptors 6Bio-R potentiated the GABAergic function, but flumazenil was still able to antagonize the potentiation induced by 6Bio-R. Aryl pyrazole derivatives activity at the GABA A receptor depends on their molecular structure. These compounds bind to both an αβγ binding site, and to an α⧸β site which do not require the γ subunit and that may provide structural leads for drugs with potential anticonvulsant effects.