New Fluoro Derivatives of the Pyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxide System: Evaluation of Fluorine Binding Properties in the Benzodiazepine Site on γ-Aminobutyrric Acid Type A (GABA_A) Receptor. Design, Synthesis, Biological, and Molecular Modeling Investigation

Abstract

In the search for potent ligands at the benzodiazepine site on the GABA(A) receptor, new fluoro derivatives of the pyrazolo[5,1-c][1,2,4]benzotriazine system were synthesized to evaluate the importance of the introduction of a fluorine atom in this system. Biological and pharmacological studies indicate that the substitution at position 8 with a trifluoromethyl group confers pharmacological activity due to potential metabolic stability in comparison to inactive 8-methyl substituted analogues. In particular, the compound 3-(2-methoxybenzyloxycarbonyl)-8-trifluoromethylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (21) emerges because of its selective anxiolytic profile without side effects. An analysis of all the newly synthesized compounds in our pharmacophoric map confirms the essential interaction points for binding recognition and the important areas for affinity modulation. The fluorine atom was able to form a hydrogen bond interaction only when it is not in position 3.

Development of ligands at γ-aminobutyrric acid type A (GABAA) receptor subtype as new agents for pain relief

“…Recently we have reported that some derivatives with the pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide core have selective anxiolytic-like properties [29][30][31][32] without exhibiting sedative and myorelaxant effects. Since the relationship between anxiolysis and antihyperalgesia is intriguing we decided to investigate the antihyperalgesic profile of some compounds we have already reported as selective anxiolytics (I, 29 II, 32 and III, 30 see Chart 1).…”

Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

“…The pyrazolobenzotriazine scaffold was first reported as a GABA A receptor ligand in 1998 [164]. During the past 10 years, N-oxide derivatives of this scaffold were synthesized and studied both in vitro and in vivo with some derivatives having binding affinities to the benzodiazepine binding site lower than 10 nM [165,166]. Some of them possess anxiolytic activity [166], which, together, suggests positive modulatory effects elicited via the benzodiazepine binding site.…”

Interaction of 4‐Oxo‐4H‐pyrazolo[5,1‐c][1,2,4]triazin‐1‐ides with Grignard Reagents

“…Azolo[5,1‐ c ][1,2,4] triazines are known to exhibit interesting reactivity and transformations and have been attracting the attention of researchers . Moreover, these compounds showed a wide range of biological activities . For example, pyrazolo[5,1‐ c ][1,2,4] triazines exhibit antiviral , antimicrobial , and antifungal activities.…”