Abstract—The synthesis and binding studies of a series of 3-acylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted are reported. High-affinity ligands at benzodiazepine site on GABAA receptor complex (GABAA/BzR complex) were obtained when the 3-aroyl substituent is represented by a five-member heteroaroyl ring (furoyl-, thenoyl-, and pyrroyl-). Moreover the type of heteroaroyl ring at position 3 influences the feature of the substituent at position 8 to obtain high-affinity ligands: a ‘hydrogen-bond acceptor ring’ at position 3 is synergic with an electron donor substituent at position 8, while a ‘hydrogen-bond donor ring’ is synergic with a withdrawing substituent. Compounds 8a, 9b, and 11 were deeply studied in vivo for their pharmacological effects considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motor activity and explorative activity, anxiolytic-like effects, mouse learning and memory modulation, and ethanol-potentiating action. To rationalize and qualitatively interpret the GABAA/Bz binding affinities of compounds 8a and 11, a dynamic molecular modeling study has been performed, with the aim of assessing the preferred geometry of protein–ligand complex.

Novel 3-aroylpyrazolo[5,1-c][1,2,4] benzotriazines 5-oxides 8-substituted, ligands at GABAA/benzodiazepine receptor complex: synthesis, pharmacological and molecular modelling studies / G. Guerrini; G. Ciciani; G. Cambi; F. Bruni; S. Selleri; F. Melani; M. Montali; C. Martini; C. Ghelardini; M. Norcini; A. Costanzo. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 1464-3391. - ELETTRONICO. - 16:(2008), pp. 4471-4489. [10.1016/j.bmc.2008.02.058]

Novel 3-aroylpyrazolo[5,1-c][1,2,4] benzotriazines 5-oxides 8-substituted, ligands at GABAA/benzodiazepine receptor complex: synthesis, pharmacological and molecular modelling studies.

GUERRINI, GABRIELLA;CICIANI, GIOVANNA;BRUNI, FABRIZIO;SELLERI, SILVIA;MELANI, FABRIZIO;GHELARDINI, CARLA;COSTANZO, ANNARELLA
2008

Abstract

Abstract—The synthesis and binding studies of a series of 3-acylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted are reported. High-affinity ligands at benzodiazepine site on GABAA receptor complex (GABAA/BzR complex) were obtained when the 3-aroyl substituent is represented by a five-member heteroaroyl ring (furoyl-, thenoyl-, and pyrroyl-). Moreover the type of heteroaroyl ring at position 3 influences the feature of the substituent at position 8 to obtain high-affinity ligands: a ‘hydrogen-bond acceptor ring’ at position 3 is synergic with an electron donor substituent at position 8, while a ‘hydrogen-bond donor ring’ is synergic with a withdrawing substituent. Compounds 8a, 9b, and 11 were deeply studied in vivo for their pharmacological effects considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motor activity and explorative activity, anxiolytic-like effects, mouse learning and memory modulation, and ethanol-potentiating action. To rationalize and qualitatively interpret the GABAA/Bz binding affinities of compounds 8a and 11, a dynamic molecular modeling study has been performed, with the aim of assessing the preferred geometry of protein–ligand complex.
2008
16
4471
4489
G. Guerrini; G. Ciciani; G. Cambi; F. Bruni; S. Selleri; F. Melani; M. Montali; C. Martini; C. Ghelardini; M. Norcini; A. Costanzo
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/321357
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