Pyridophens:  Binary Pyridostigmine−Aprophen Prodrugs with Differential Inhibition of Acetylcholinesterase, Butyrylcholinesterase, and Muscarinic Receptors

Abstract

A series of "binary prodrugs" called carbaphens,(1) carbamylated derivatives on one or both of the aromatic rings of the muscarinic receptor antagonist aprophen [(N,N-diethylamino)ethyl 2,2-diphenylpropionate], were synthesized to develop binary prophylactic agents against organophosphorus intoxication. As a group, the carbaphens retained the muscarinic receptor antagonist properties of aprophen but also preferentially inhibited butyrylcholinesterase (BChE) in contrast to acetylcholinesterase (AChE). Therefore, a new series of compounds named pyridophens were designed and synthesized to achieve binary prodrugs to preferentially inhibit AChE over BChE, while still retaining the muscarinic receptor antagonism of aprophen. The pyridophens consist of the basic pyridostigmine skeleton combined with the 2,2-diphenylpropionate portion of aprophen by replacement of the diethylamino group. Three compounds, 9 (a tertiary pyridine), 10 (a quaternary pyridine), and 12 (a tertiary tetrahydropyridine), were found to be effective inhibitors of both BChE and AChE. However, 10, N-methyl-3-[[(dimethylamino)carbonyl]oxy]-2-(2'2'-diphenylpropionoxy-methyl)pyridinium iodide, inhibited AChE selectively over BChE, with a bimolecular rate constant similar to pyridostigmine. In contrast to their potent cholinesterase inhibitory activity, all of the pyridophen analogues were less potent antagonists of the muscarinic receptor than aprophen.

Synthesis of α-oxycarbanilinophosphonates and their anticholinesterase activities: the most potent derivative is bound to the peripheral site of acetylcholinesterase

“…Although we have not tried out to determine the inhibition mechanism, considering the fact that it can be deduced from molecular modelling results that the mode of inhibition is of mixed type inhibition, in the case of pure noncompetitive inhibition, K i would be equal to IC 50 , that is 6.36 µM 35 . This deduced K i of compound 4h is comparable to and in a number of cases more potent than reported K i 's for synthetic anticholinesterases in the literature [36][37][38] . The presence of two chlorine atoms at ortho and para positions of the aromatic ring has made the ring very electrondeficient and consequently well prepared for potential π-π interactions with aromatic side chains in the PAS.…”

Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

“…The cellinactive but animal toxic pancuronium is a non-depolarizing muscle relaxant inhibiting the nicotinic acetylcholine receptor. Neostigmine [45], pyridostigmine [46] and physostigmine are reversible inhibitors of cholinesterase; physostigmine can penetrate the blood-brain barrier. The examples in Fig.…”

Specific inhibition of acetylcholinesterase as an approach to decrease muscarinic side effects during myasthenia gravis treatment

“…Maximum effect of C547 on muscle contraction was significantly lower than maximum effect of pyridostigmine. From our previous biochemical experiments we learnt, that at 10 nM C547 significantly inhibits AChE 13 , but not BChE; 1 μM of pyridostigmine completely blocks both ChEs 20 . Thus, one could hypothesize that it was just inhibition of BChE that accounts for the difference seen in the maximum effects of C547 and pyridostigmine.…”