Synthesis and pharmacological activity on Electrophorus electricus electroplaque of photoaffinity labelling derivatives of the non‐competitive blockers di‐ and tri‐methisoquin

The physiological response of the neuromuscular junction, or of the fish electroplaque, to acetylcholine (ACh) is blocked by two distinct classes of pharma- cological agents [ 11. The competitive antagonists such as d-tubocurarine or flaxedil bind at the level of (or close to) the receptor site for acetylcholine where they block the effect of the agonists possibly by steric hin- drance. This site is also labelled by snake venom a-toxins 123 and the covalent affinity labelling reagents: TDF [3,4]; MPTA [S]; bromoacetylcholine [6]; DAPA [7]. Another rather heterogeneous group of compounds includes the aminated local anesthetics [1,8] and the frog toxin, histrionicotoxin [9,10], which block the response to ACh in a non-competitive manner. In vitro studies carried out with radioactive [8,1 l-131 or fluorescent [12,14-181 ligands have shown that these non-competitive blockers bind to a class of sites distinct from the ACh-receptor site [ 11, 121. Moreover, at equilibrium [ 121 or after rapid mixing [ 14,17,18] the two classes of sites have been shown to interact in an allosteric manner. Biophysical experiments suggest that these non-competitive blockers bind directly to the ion gate opened by ACh [ 19,201, although indirect effects are also possible [21]. In any case, compounds of this series behave as