Molecular basis of interactions of cholinesterases with tight binding inhibitors

Synthesis of a novel series of non-symmetrical bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase

“…The results confirm that the position of hydroxyiminomethyl groups influences the reactivation potency [30 -33]. In this case, compounds bearing oxime groups in positions 3-4 (6, 9, 12) and 3-3 (14,17,20) were almost ineffective, compounds with oxime groups in positions 2-3 (7, 10), 2-4 (8, 11), 2-2 (16, 19) and 4-4 (15,18,21) showed satisfactory reactivation ability against paraoxon-inhibited AChE. Another important factor for reactivation potency is the structure of the connecting chain as was discussed previously [14 -16].…”

“…In order to fix the conformation of the molecule, we decided to use a xylene linker connecting two pyridinium rings bearing oxime moieties non-symmetrically (nine novel compounds, 4-12), in contrast with symmetrical ones (nine compounds prepared previously, 13-21) [16]. The idea and design of an aromatic linker was used by comparison with inhibitors of AChE with a triazole linker prepared using click chemistry methods [17][18]. Moreover, each position of oxime on the pyridinium ring is able to reactivate another type of inhibitor.…”

Synthesis of monooxime-monocarbamoyl bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against tabun- and paraoxon-inhibited acetylcholinesterase

“…The cavity contains one catalytic (acylation, A) site at the bottom and one peripheral site (P) at the lip of the cavity [11 -12]. The A-site contains the catalytic triad (for human AChE, S203, E334 and H447) which together with W86 is responsible for binding of the trimethylammonium group of acetylcholine as acyl transfer to Ser203 is initiated [13]. The P-site involves other residues including W286 [14].…”

Signalling in response to sub‐picomolar concentrations of active compounds: Pushing the boundaries of GPCR sensitivity

“…The contractile response to ultra-low concentrations of Ang II could be inhibited by 1 fM of a competitive antagonist, Sar 1 ,Ala 8 -Ang II (saralasin; Kuttan & Sim, 1991). This inhibition was not competitive, but this would fit with the biophysical implications of femtomolar affinity binding, such that the dissociation rate should be so slow as to be essentially irreversible (Radić et al, 2005;Yang et al, 2007). Under these conditions, a classically defined competitive antagonist would not be expected to behave in a competitive manner.…”