Evaluation of the side arm of (naphthylvinyl)pyridinium inhibitors of choline acetyltransferase

Abstract

A number of quaternary salts of trans-4-(beta-1-naphthylvinyl)pyridine (NVP) were synthesized and evaluated as inhibitors of the enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). Structural variations in the side arm attached to the pyridine nitrogen atom demonstrate that an inductive effect is small but significant for activity. Inhibition of ChAT by alkylated derivatives decreases when electron-withdrawing groups are placed in the side chain. Substitution of a methyl group on the pyridine ring only slightly affects activities toward ChAT and AChE. When the pyridinium moiety is replaced by an imidazolium ring, no ChAT inhibition was observed. The imidazolium compound, however, was a weak inhibitor of AChE. For design of affinity columns for purification of ChAT, the data also supports the use of long chain alkylated amide derivatives of NVP.

Three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses of choline acetyltransferase inhibitors

“…Several of these variables have been identified or proposed for the a-b-c-d components of the molecule and for the molecule as a whole [10]. Component b which is a trans-vinyl linkage and component d which primarily serves to quaternize the N atom, do not appear to be structurally specific [23]. This leaves the burden of establishing optimum structural parameters on a and c.…”

In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design

“…The in situ assembled ligand exhibits excellent shape complementarity towards the interfacial active‐site tunnel formed between the binding and catalytic domains of ChAT. Over 160 different AVPs and some analogous compounds with inhibitory activity against ChAT have been reported [9, 22–29] but no structural information about their interaction with ChAT is available. Our crystal structure shows that 1‐CoA spans the choline and AcCoA binding sites of ChAT, with the electron‐deficient pyridinium ring of 1‐CoA forming an edge‐to‐face interaction with the arene of Tyr552 and additional contacts to His324, Tyr436 and Ser438 (Figure 3 A).…”

“…The conformation of the His324 sidechain differs from that in the apo-and holoenzyme, [20] and the structure suggests that the imidazole activates the thiol of CoA towards nucleophilic attack on the alkene moiety of 1.A ccordingly,t he site of His324-assisted activation in the enzymatic synthesis of 1-CoA differs from that in the natural reaction of ChAT, where the imidazole instead activates choline.The in situ assembled ligand exhibits excellent shape complementarity towards the interfacial active-site tunnel formed between the binding and catalytic domains of ChAT. Over 160 different AV Ps and some analogous compounds with inhibitory activity against ChAThave been reported [9,[22][23][24][25][26][27][28][29] but no structural information about their interaction with ChATi sa vailable.O ur crystal structure shows that 1-CoA spans the choline and AcCoA binding sites of ChAT, with the electron-deficient pyridinium ring of 1-CoA forming an edge-to-face interaction with the arene of Ty r552 and additional contacts to His324, Ty r436 and Ser438 (Figure 3A). Then aphthyl moiety of 1-CoA is accommodated in ah ydrophobic pocket with contacts to residues Pro98, Cys322, Leu332, Va l542, Cys550, Ty r552, and Cys563 (Figure 3B).…”

Synthesis of new vinylpyridinium salts

“…1). The main interest in these lies in their structural similarity to those described by DeBernardis et al , and therefore their potential to inhibit CAT and AChE [9]. DeBernardis et al .…”