Differential modulation of GABA(A) receptor function by aryl pyrazoles.
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 α1β2γ2L GABAA 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 GABAA receptor function, but they acted as antagonists of 6Bio-R. Moreover, NESS 0327 inhibited the potentiation of the GABAA 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 GABAA 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 α1β2 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 GABAA 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.
CNR - Institute of Neuroscience, Cittadella Universitaria, 09042 Monserrato, Italy. Electronic address: mascia@in.cnr.it.
Maria Paola
MP
Mascia
Department of Life and Environmental Science, Center of Excellence for the Neurobiology of Dependence, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
Giovanni
G
Ledda
CNR - Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy.
Alessandro
A
Orrù
Department of Life and Environmental Science, Center of Excellence for the Neurobiology of Dependence, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
Alessandro
A
Marongiu
CNR - Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy.
Giovanni
G
Loriga
CNR - Institute of Neuroscience, Cittadella Universitaria, 09042 Monserrato, Italy.
Elisabetta
E
Maciocco
CNR - Institute of Neuroscience, Cittadella Universitaria, 09042 Monserrato, Italy; Department of Life and Environmental Science, Center of Excellence for the Neurobiology of Dependence, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
Giovanni
G
Biggio
CNR - Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy.
Stefania
S
Ruiu
D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D018757:GABA Modulators / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D014162:Transfection; D014982:Xenopus laevis
D018757:GABA Modulators; D008024:Ligands; D021122:Protein Subunits; D011720:Pyrazoles; D011963:Receptors, GABA-A; D011994:Recombinant Proteins
Aryl pyrazoles; Aryl pyrazoles (PubChem (Ness 0327) CID 10435654); Benzodiazepines; Benzodiazepines (PubChem CID 134664); GABA(A) receptor