Prophylaxis against
organophosphate poisoning can be achieved by pretreatment with
physostigmine or
pyridostigmine, which are
carbamates, and
aprophen, which is an
anticholinergic agent. Thus, a series of
aprophen analogues was synthesized with carbamyl substitutions on the phenyl rings (carbaphens). The rationale behind this design is that such compounds might exhibit most of the therapeutic characteristics of
aprophen, as well as the ability to protect prophylactically by chemically masking
cholinesterase enzymes. Compounds 4 (dimethylhydroxycarbaphen), 15 (dimethylcarbaphen), and 16 (monomethylcarbaphen) were found to inactivate human
butyrylcholinesterase in a time-dependent manner with potencies similar to those of
physostigmine or
pyridostigmine, and the latter two exhibited almost the same
antimuscarinic profile as
aprophen. In contrast to the potent inactivation of
butyrylcholinesterase by these compounds, marginal inactivation of
acetylcholinesterase activity was observed, and only at much higher
drug concentrations. The noncarbamylated analogues had no effect on the activity of either
cholinesterase. The carbaphen compounds are hence prototype drugs that can interact with either
muscarinic receptors or
butyrylcholinesterase. Furthermore, these compounds are
prodrugs, since after carbamylation of the
cholinesterase, the leaving group 14 (hydroxyaprophen) is a potent
antimuscarinic itself.