3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones:  Tricyclic Heteroaromatic Derivatives as a New Class of Benzodiazepine Receptor Ligands

Abstract

A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended directly on the presence of the N(10)-H group and an aromatic ring at position 3. Some of them elicited a 2- or 3-fold higher affinity with respect to that of the indolylglyoxylylamide derivatives IV (R = H). The GABA ratio and [(35)S]-tert-butylcyclophosphorothionate binding data revealed an efficacy profile of partial inverse agonists/antagonists for compounds 1c,e,f,j,k, and of a partial agonist for 2c. This last compound proved to be effective in antagonizing pentylenetetrazole-induced seizures in mice. Attempts were made to interpret the structure-affinity relationships of compounds V in the light of possible tautomeric equilibria involving the ligands.

Geometrically Constrained Analogues of N‐Benzylindolylglyoxylylamides: [1, 2, 4]Triazino[4, 3‐a]benzimidazol‐4(10H)‐one Derivatives as Potential New Ligands at the Benzodiazepine Receptor

“…Moreover, these results unequivocally demonstrated that for TBI derivatives, N(10)-H represents one of the necessary groups for interaction with the receptor site, as previously hypothesized by us [11].…”

“…The structure of compound 18 was confirmed by comparing its physical and spectral data with those of the 10-methyl isomer 15 and previously described similar products [11]. Actually, in the 1 H-NMR 18…”

“…We have previously hypothesized that for these types of products, the tautomeric form A is the active one, since it features the N(10)-H group which, according to our hypothesis, donates a hydrogen bond to the A2 site of the BzR (see the pharmacophoric scheme in Figure 1) [11].…”

“…ligands: the 3-aryl [1,2,4]triazino [4,3-a]benzimidazol-4(10H)-ones III (ATBIs) (Chart 1) [11].The triazinobenzimidazole (TBI) nucleus represents a geometrically constrained system with respect to the indolylglyoxylyl moiety of compounds II, the oxalyl CO(2) oxygen of II being replaced by the N(2) of TBI.…”

3-(Fur-2-yl)-10-(2-phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a Novel Adenosine Receptor Antagonist with A2A-Mediated Neuroprotective Effects

“…It involves the synthesis of 2-chloro-1-(2-phenylethyl)benzimidazole 2 by alkylation of the commercially available 2-chlorobenzimidazole 1 with 2-bromoethylbenzene in the presence of sodium hydride. 38 Heating 2 with hydrazine hydrate at 180°C in a Pyrex capped tube yielded the 2-hydrazone derivative 3, that was allowed to react in refluxing ethanol with (fur-2-yl)oxoacetic acid for 2 h. In agreement with our previous findings, 31,39 the obtainment of the target tricyclic compound FTBI proceeded through the formation of the intermediate 2-(benzimidazol-2-ylhydrazono)-2-furyl acetic acid 4 which was separated by cooling of the reaction mixture. It was isolated by filtration and purified by suspension in hot methanol.…”