The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

Abstract

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1–4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

“…Both compounds also slightly induced CYP2D6 (Figure 7b). In summary, the compounds showed very low or no risk of DDIs in comparison to the reference inhibitors quinidine and ketoconazole, a results that correlates with previous data obtained for another 5-HT 6 R ligands from the group of 1,3,5-triazine-methylpiperazines [22]. Apart from the number of metabolites found, the predominant amount of untransformed substrates, either KMP-10 or DJ-18, was confirmed by the analyses, which were able to prove the good metabolic stability of both compounds.…”

“…Compound DJ-18, with its p-chlorobenzyl substituent, had an excellent,~1.65 stronger ability to penetrate the artificial membrane than high-permeable reference caffeine, whereas KMP-10, with a naphthyl substituent, showed a~4-fold weaker permeability than caffeine ( Table 2). The result for DJ-18 confirmed our previous data, where the triazine-based 5-HT 6 R ligand with the presence of chlorobenzyl moiety (Compound 1 in the reference [22]) was also shown as highly permeable compound in PAMPA (Pe = 23.6 × 10 −6 cm/s). Permeability Assay with Using Caco-2 Cells…”

“…Both compounds also showed a long biological half-life (t 1/2 ) that was~6-fold (DJ-18) and~8-fold (KMP-10) longer than the reference-the unstable drug verapamil ( Table 2). The observed good pharmacokinetic properties correspond with results of the previously tested 5-HT 6 R triazine ligands (with a CL int value also below 8.6 mL min −1 kg −1 ) [22]. In this context, the properties of KMP-10 were even better than those of the most active 5-HT 6 R agent found earlier, the thymol-1,3,5-triazine derivative MST4 (4 in the reference [22]), and in the range of the indolemethyl triazine derivative (3 in the reference [22]).…”

“…Moreover, the similar main metabolic pathway-demethylation at the N-methylpiperazine moiety (the M1 metabolite) was determined for both the 5-HT 6 R ligands by MS and MS/MS analyses (Table 3; Figures S1-S4 in Supplementary Information). That reaction was also predicted by MetaSite with the highest, 100% probability (data not shown) and was observed in our previous investigations on the metabolism of 1,3,5-triazine-methylpiperazine derivatives [22,27]. Other metabolic pathways included hydroxylations (both compounds) and dehydrogenation (KMP-10).…”

“…The results obtained for 5-HT 6 R ligands indicated that none of the tested compounds was the substrate of Pgp because they did not increase the Pgp activity at the tested concentration 100 µM, nor did they did cause any statistically significant changes of basal Pgp activity. No strong substrate of Pgp among triazine-derived 5-HT 6 R ligands had been found in our previous studies as well [22]. One of the most significant modification strategies for brain penetration improvement is reducing P-glycoprotein (Pgp) efflux.…”