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 |
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Authors: | Guerrini Gabriella Costanzo Annarella Ciciani Giovanna Bruni Fabrizio Selleri Silvia Costagli Camilla Besnard François Costa Barbara Martini Claudia De Siena Gaetano Malmberg-Aiello Petra |
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Institution: | Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via U. Schiff, 6, 50019 Polo Scientifico, Sesto Fiorentino, Florence, Italy. gabriella.guerrini@unifi.it |
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Abstract: | The synthesis and the binding study of new 3-arylesters and 3-heteroarylpyrazolo5,1-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. |
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