Novel 3-iodo-8-ethoxypyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide as promising lead for design of α5-inverse agonist useful tools for therapy of mnemonic damage

Article abstract of DOI:10.1016/j.bmc.2007.01.053

The synthesis and the binding study of new 3-iodiopyrazolo[5,1-c][1,2,4] benzotriazine 5-oxides 8-alkyloxy substituted are reported. The replacement at position 3 with an iodine atom, with respect to substituents capable to form a three centered hydrogen bond and/or to form π-π stacking interaction with receptor protein, gave high affinity ligands, independently of the 8-alkyloxy substituent. High-affinity ligands were studied in mice in vivo for their pharmacological effects, considering five potential benzodiazepine actions: anxiolytic-like effects, motor coordination, anticonvulsant action, mouse learning and memory impairment, and ethanol-potentiating action. Compounds 5c and 5′c have an inverse agonist profile and for the first time is evidenced a pro-mnemonic activity. These compounds were evaluated also for their binding at Benzodiazepine site on GABA_A receptor complex (GABA_A/BzR complex) subtype to evaluate their subtype selectivity.