The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

Abstract

Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor.. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

“… The structural variety of 5-HT 6 R antagonists: ( a ) compounds 1 [ 23 , 24 ], 2 [ 25 ], 3 [ 26 , 27 , 28 , 29 ], 4 [ 30 , 31 , 32 ] and 5 [ 33 ] investigated in clinical trials; ( b ) compounds in the early stages of R&D: the non-indole and non-sulfone derivatives 6 [ 34 ], 7 [ 35 ], 8 [ 36 , 37 ], 9 [ 38 , 39 ], 10 [ 40 , 41 ]and 11 [ 42 ] and non-basic antagonists 12 [ 43 ] and 13 [ 43 , 44 ]. The affinity for 5-HT 6 R expressed with K i (nM).…”

“…Procognitive effects in the Novel Object Recognition (NOR) test for 8–10 . at the dose shown [ 36 , 37 , 38 , 39 , 40 , 41 ].…”

“…On the other hand, the chemical space of 5-HT6R ligands is rather narrow, predominantly mapped by sulfonamide, indole and indole-like moieties, also containing a basic center most often represented by N-unsubstituted-or N-methylpiperazine (Figure 1). [23,24], 2 [25], 3 [26][27][28][29], 4 [30][31][32] and 5 [33] investigated in clinical trials; (b) compounds in the early stages of R&D: the non-indole and non-sulfone derivatives 6 [34], 7 [35], 8 [36,37], 9 [38,39], 10 [40,41]and 11 [42] and nonbasic antagonists 12 [43] and 13 [43,44]. The affinity for 5-HT 6 R expressed with K i (nM).…”

“…Recent research results have contributed to increasing the chemical diversity of 5-HT 6 R ligands. Apart from the structures of quinoline-2,4-diones (6) [34] and asenapine (7) [35] described in 2008-2009, the last five years have also provided non-indole and non-sulfonic derivatives of triazine (8, 9) [36][37][38][39], hydantoin (10) [40,41], imidazopyridine (11) [42], as well as non-basic 5-HT 6 R ligands (12,13) [43,44], which also showed procognitive activity in animal models (8)(9)(10), promising for potential AD therapies (Figure 1b).…”

“…The affinity for 5-HT 6 R expressed with K i (nM). Procognitive effects in the Novel Object Recognition (NOR) test for 8-10. at the dose shown[36][37][38][39][40][41].…”