Benzodiazepine receptor ligands. 8: synthesis and pharmacological evaluation of new pyrazolo[5,1-c] [1,2,4]benzotriazine 5-oxide 3- and 8-disubstituted: high affinity ligands endowed with inverse-agonist pharmacological efficacy.
The synthesis and the binding study of new 3-arylesters and 3-heteroarylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 8-substituted are reported. The nature of these substituents (in terms of lipophilic and electronic features) seems to influence the binding affinity. High-affinity ligands were studied in mice in vivo for their pharmacological effects, considering six potential benzodiazepine actions: anxiolytic-like effects, muscle relaxant effects, motor coordination, anticonvulsant action, spontaneous motor activity, and ethanol-potentiating action. Compounds 4d and 6d showed an inverse-agonist profile. These compounds were evaluated also for their binding at benzodiazepine site on GABAA receptor complex (GABAA/BzR complex) subtype to evaluate their subtype selectivity.
Guerrini
Gabriella
G
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via U. Schiff, 6, 50019 Polo Scientifico, Sesto Fiorentino, Florence, Italy. gabriella.guerrini@unifi.it
Costanzo
Annarella
A
Ciciani
Giovanna
G
Bruni
Fabrizio
F
Selleri
Silvia
S
Costagli
Camilla
C
Besnard
François
F
Costa
Barbara
B
Martini
Claudia
C
De Siena
Gaetano
G
Malmberg-Aiello
Petra
P
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002417:Cattle; D005442:Flumazenil / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D008024:Ligands; D011963:Receptors, GABA-A; D014227:Triazines; D005442:Flumazenil