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Monday, March 10, 2008

Novel 3-aroylpyrazolo[5,1-c][1,2,4]
benzotriazine 5-oxides 8-substituted, ligands at GABAA/benzodiazepine receptor complex: Synthesis, pharmacological and molecular modeling studies

Bioorganic & Medicinal Chemistry Article in Press, Corrected Proof 5 March 2008

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.

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