Abstract

Several series of acyl analogs of acetylcholine (including fluorescent ones) were synthesized and their pharmacological properties investigated on Electrophorus electricus electroplaque. Their action as agonist, noncompetitive blocker, or mixed agonist-noncompetitive blocker depends both on the nature of the N-terminal substituent and on the length of the alkyl chain. The C₁, C₂, and C₃ members of the dansylamidoacyicholine (C_nDAChol) and naphthylsulfonamidoacylcholine (C_nAChol) series behave as noncompetitive blocking agents, while the C₄, C₅, and C₇ analogs exhibit a significant agonist character in addition to their noncompetitive effect. This difference might result from the folding of the ammonium group on top of the aromatic ring which would prevent access of the C₁ to C₃ members of the series to the agonist binding site. The C₁₀DAChol and NAChol are powerful noncompetitive blockers and, at variance with other members of the series, form micelles in aqueous solution. Replacement of the N-terminal aromatic ring by a polar alkyl group (as in methylsulfonamidoacylcholine) abolishes the noncompetitive blocking properties and yields a series of potent full agonists. The apparent affinity of the agonists thus obtained increases with the length of the polymethylene spacer. The partial agonistic character of some of the compounds synthesized is interpreted as resulting from their dual pharmacological action as agonists and noncompetitive blockers binding to two distinct classes of membrane sites.