A novel selective GABA(A) alpha1 receptor agonist displaying sedative and anxiolytic-like properties in rodents.
In our pursuit to identify selective ligands for Bz/GABA(A) receptor subtypes, a novel pyrazolo[1,5-a]pyrimidine derivative (4), the azaisostere of zolpidem, was synthesized and evaluated in vitro on bovine brain homogenate and on recombinant benzodiazepine receptors (alphaxbeta2/3gamma2, x = 1-3, 5) expressed in HEK293 cells. Compound 4 displayed affinity only for alpha1beta2gamma2 subtype (K(i) = 31 nM), and in an in-depth, in vivo study it revealed sedative and anxiolytic-like properties without any amnesic and myorelaxant effects in rodents.
Selleri
Silvia
S
Department of Pharmaceutical Sciences, University of Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino, Italy. silvia.selleri@unifi.it
Bruni
Fabrizio
F
Costagli
Camilla
C
Costanzo
Annarella
A
Guerrini
Gabriella
G
Ciciani
Giovanna
G
Gratteri
Paola
P
Besnard
François
F
Costa
Barbara
B
Montali
Marina
M
Martini
Claudia
C
Fohlin
Jonna
J
De Siena
Gaetano
G
Aiello
Petra Malmberg
PM
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D058785:GABA-A Receptor Agonists; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A; D011994:Recombinant Proteins / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; C546240:GABRA1 protein, human; C546241:Gabra1 protein, mouse; D006993:Hypnotics and Sedatives; C505985:N,N-dimethyl-(2-(4-methylphenyl)-5-methylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins