Pyrazolo[1,5-a]quinazoline scaffold as 5-deaza analogue of pyrazolo[5,1-c][1,2,4]benzotriazine system: synthesis of new derivatives, biological activity on GABA_A receptor subtype and molecular dynamic study

Abstract

To investigate the binding affinity of GABAA receptor subtype, new pyrazolo [1,5-a]quinazolines were designed, synthesized, and in vitro evaluated. These compounds, 5-deaza analogues of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives which were already studied in our research group, permit us to evaluate the relevance of the nitrogen or the oxygen atom at 5-position of the tricyclic scaffold. Molecular dynamic study was done on a set of the new and known ligands to rationalize and to explain the lack of affinity on the 4- or 5-substituted new derivative. In fact, from biological results, it can be found that the only 5-unsubstituted new derivative, compound 15, has receptor recognition (Ki = 834.7 nM).

Identification of a New Pyrazolo[1,5-a]quinazoline Ligand Highly Affine to γ-Aminobutyric Type A (GABAA) Receptor Subtype with Anxiolytic-Like and Antihyperalgesic Activity

“…24 Moreover, very interesting is the evidence that the α4 and α5subunits are expressed in airway smooth muscle (ASM), therefore this GABA A -R subtypes represent a compelling pharmacological target to achieve bronchodilation in asthma, and both α4 and α5 GABA A -R positive allosteric modulators could be able to relax precontracted ASM. 25,26 Continuing our study on GABA A -Rs subtype ligands, in our previous work, we synthesized a series of compounds with pyrazolo[1,5-a]quinazoline (PQ) 27 scaffold as 5-deaza analogues of the pyrazolo[5,1-c][1,2,4]benzotriazines (PBT), endowed with anxiolytic, antihyperalgesic, 18,28 or procognitive activity, 21 Chart 1. In the new 5-deaza-scaffold, the disubstitution at 3,4 or 3,5 positions gave compounds lacking of receptorial recognition, and the only compound exhibiting binding affinity is the ethyl pyrazolo[1,5-a]quinazoline 3carboxylate 27 showing a completely aromatized tricyclic system.…”

New 3,6‐Disubstituted Pyrazolo[1,5‐a]quinazolines as Ligands to GABAA Receptor Subtype

“…Despite the presence, in this new series, of substituents already identified for the 8-PQ [19] and for pyrazolo [5,1-c] [1,2,4]benzotriazine [22,23], as important to form hydrogen bond interaction (oxygen atom of methoxy or benzyloxy group) or to form π-π interactions with lipophilic area in the receptor (iodine or arylalkylester moiety), the movement of these substituents from position 8 to position 6 is detrimental for binding. On the other hand, our previous study of the pyrazoloquinazoline system clearly showed that also the introduction of substituents at position 5 led to the loss of binding recognition [18].…”

“…Continuing our study on GABA A -Rs subtype ligands, we focalized our attention on compounds with pyrazolo [1,5-a] quinazoline (PQ) scaffold as 5-deaza analogues of the potent pyrazolo [5,1-c] [1,2,4]benzotriazines, previously identified by our research group as high affinity GABA A -R subtype ligands [10,13,16,17]. We first synthesized pyrazolo[1,5-a]quinazoline and 4,5-dihydropyrazolo [1,5-a] quinazoline variously substituted at 3-position and/or 8-position [18,19]. The most interesting compounds showing K i values in the (sub)nanomolar range (0.27-34 nM) were the 8-methoxypyrazolo[1,5-a]quinazoline 3-(hetero)arylester derivatives, both in the dehydro form and in the dihydro form.…”

Synthesis and Pharmacological Evaluation of Novel GABAA Subtype Receptor Ligands with Potential Anxiolytic‐like and Anti‐hyperalgesic Effect

“…The same trend is verified also in the 3‐triazole derivatives ( 18a and 21a ). All these molecules will be inserted in a next study of molecular dynamic to evaluate the occurrence of hydrogen bonds and Van der Walls interactions, between the ligand and the amino acids of receptor protein .…”