Distance geometry of alpha-substituted 2,2-diphenylpropionate antimuscarinics.

Quantitative structure-activity relationships between pharmacological activities and physical properties of a series of 2,2-diphenylpropionate compounds were used to define the topography of the antagonist binding site of muscarinic receptors. XICAMM, a computer molecular modeling program, was used to calculate geometrical and topological values of the compounds. The compounds were tested for their antimuscarinic activities by: (a) inhibition of [N-methyl-3H]scopolamine binding to the muscarinic receptors of N4TG1 neuroblastoma cells, (b) inhibition of carbachol-induced alpha-amylase release from rat pancreas acini, and (c) blocking of acetylcholine-induced contraction of guinea pig ileum. To evaluate as clearly as possible only the effect of the bond distance on the potency of the synthesized antimuscarinics, the compounds contained as many constant features as possible. Neither the hydrophobic nor the ester moieties of the compounds were changed, and the rings containing the protonated nitrogen were saturated and restricted. The antimuscarinic activities obtained from the three assays were significantly correlated with each other, with the exception of two compounds, 9 and 13. The latter two compounds demonstrated specificity for the m3 muscarinic receptor subtype expressed in the pancreas. Furthermore, it was demonstrated that the antimuscarinic activities were significantly related to the bond distances between the carbonyl oxygen (constant electronegative locus) and the protonated nitrogen (center of cationic charge) of the 2,2-diphenylpropionate compounds. Parabolic relationships between the pharmacological activities and bond distances were empirically established. The shortest calculated bond distance of these compounds was approximately 4.4 A, whereas the longest was about 5.9 A. The maximum antimuscarinic potency was observed with a calculated bond distance of about 5.2 A in all three assays.

Binary antidotes for organophosphate poisoning: aprophen analogues that are both antimuscarinics and carbamates.

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.

6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.

The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.