Structural correlations of choline acetyltransferase inhibitors: trans-N-(carboxymethyl)-4-(.beta.-1-naphthylvinyl)pyridinium bromide and cis-N-(2-aminoethyl)-4-(.beta.-1-naphthylvinyl)-3-methylpyridinium bromide hydrobromide

Abstract

This paper correlates the X-ray structures of two 4-(beta-1-naphthylvinyl)pyridine analogues (one cis and one trans) with chemical and biological activity data for this class of cholineacetylase inhibitors. Our results suggest that one of the two proposed mechanisms for inhibition by this class of compounds better describes their efficacy. Previous arguments about coplanarity of the aromatic rings and nucleophilicty across the vinyl linkage need to be modified. Quantum calculations are also included and substantiate previous suggestions about the charge distribution across the vinyl linkages. An alternate new mechanism of inhibition is proposed to encompass the published data and more recent results discussed in this paper.

Interaction of tetrahydrostilbazoles with monoamine oxidase A and B

“…Similar observations were reported in a previous study of styrylpyridinium cations with the semiempirical method MNDO. 16 In contrast to the linear trons-MTHS, the adoption of a coplanar conformation by cis-MTHS is clearly disfavored, owing to unfavorable steric interactions. Steric congestion in this structure is relieved by the adoption of a conformation which contains minimal extended conjugation.…”

“…These results are consistent with those reported earlier for styrylpyridinium cations. 16 The Transto Cis Isomerization. As noted in a recent paper,10 the oxidation of 4a, the unsubstituted trans-MTHS, by MAO A is characterized by nonlinear Lineweaver-Burke plots.…”

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

“…While AVPs are reasonably potent in vitro , their confounding pharmacological profile, [10, 11] their propensity to photoisomerize, [12] their electrophilic scaffold, and their permanent charge limits their usefulness in many applications. Furthermore, the mechanism of ChAT inhibition by AVPs is hitherto unknown, [13–15] and the structure–activity relationships (SAR) of these compounds have yielded few clues as to how they could be improved [16] . In addition to AVPs, aryl‐3‐oxopropanaminium compounds (e.g alfa ‐NETA) are known inhibitors of ChAT, [17] and a recent work by Darreh‐Shori and co‐workers have identified commercially available compounds by virtual screening that show inhibitory activity in in vitro assays [18, 19] …”

“…[6] ChATisalso apotential target for pharmacotherapy for ar ange of medical conditions,including blood pressure disorders [7] and cholinergic overstimulation caused by organophosphorus nerve agents; [8] however, validation of ChATs utility as ad rug target has not been possible due to the lack of useful inhibitors.A rylvinylpyridiniums (AVPs,f or example the prototypical compound 1,F igure 1) are the most widely studied ChATi nhibitors,w ith reported half maximal inhibitory concentrations (IC 50 )i nt he low micromolar range. [9] While AV Ps are reasonably potent in vitro,their confounding pharmacological profile, [10,11] their propensity to photoisomerize, [12] their electrophilic scaffold, and their permanent charge limits their usefulness in many applications.F urthermore,the mechanism of ChATinhibition by AV Ps is hitherto unknown, [13][14][15] and the structure-activity relationships (SAR) of these compounds have yielded few clues as to how they could be improved. [16] In addition to AV Ps,a ryl-3-oxopropanaminium compounds (e.g alfa-NETA) are known inhibitors of ChAT, [17] and ar ecent work by Darreh-Shori and coworkers have identified commercially available compounds by virtual screening that show inhibitory activity in in vitro assays.…”

Molecular Modeling Studies of Some Choline Acetyltransferase Inhibitors

“…There exists spectral evidence to support some deviation from the planar configuration of both the truns-naphthylvinylpyridinesg and the structurally similar trans-styrylnaphthalene.1° A relatively shallow energy profile has been reported for trans-stilbene with a minimum lying 0.7 kcaymol lower than the planar conformation.ll Furthermore, an analog of I in the crystalline state was found to show a 12" deviation from planarity of the aromatic-conjugated system. 12 In an attempt to correlate activity with the preferred conformations of the compounds in Figure 1, conformational searches using the semiempirical and molecular mechanics methodologies were utilized.…”