Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H3 and dopamine D3 receptors

Abstract

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H₃ and dopamine D₃ receptors (H₃R and D₃R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H₃R and D₃R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the K_i and IC₅₀ values. Results showed that several compounds were ligands at H₃R (n = 10), D₃R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (K_i H₃R 2.8 µM; D₃R 0.7 µM; IC₅₀ BChE 26.3 µM) and LINS05015 (K_i H₃R 1.1 µM; D₃R 3.1 µM; IC₅₀ AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties.

Keywords: Cholinesterase inhibitors; D(3)R ligand; H(3)R ligand; Multitarget ligand; Procognitive agents.