Molecular Pharmacological Studies on Drug-Receptor Complexes System in Drug Action. IV. Relationship between Anticholinergic and Anticholinesterase Activities of Organophosphoryl Choline Derivatives based on their Chemical Structure

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To clarify the relationship between anticholinergic and anticholinesterase (anti-ChE) activities on the basis of chemical structure, nineteen organophosphoryl choline derivatives [chemical formula] were synthesized. Curare-like, atropine-like and anticholinesterase actions of these compounds were tested to screen. The experimental results were as follows : 1) Curare-like and atropine-like actions were both studied by Magnus method, observing their effect on rectus abdominis of frog and on intestines of white mice. Anti-ChE action on enzyme preparation from rabbit serum was tested by using Warburg's manometric method. 2) As to the basic structure of various organophosphoryl choline derivatives, curarelike action was increased in the following order of magnitude ; [chemical formula]. The R radicals increased the potency in the following order ; [chemical formula] and as for quaternary ammonium salts of derivatives, bromides were more potent than iodides. From these compounds it was found that four derivatives of NP-244 (I), NP-245 (I), NP-244pC (I) and NP244pB (I) was more potent than curare. 3) On the atropine-like action of organophosphoryl choline derivatives, the relation between their structure and potency was found to have the same tendency as in the case of curare-like action, but all of these derivative were weaker than that of atropine. 4) On the anti-ChE action of organophosphoryl choline, the basic structures increased its potency in the following order ; [chemical formula], but the change in R radicals did not always increase the potency of their curare-like action. All of these derivatives were weaker than neostigmine. 5) The relationship between curare-like and atropine-like actions and between curare-like and anti-ChE actions were discussed with the selective indexes calculated from experimental results. Some of thionothiol-phosphate have both curare-like and ChE activity, and its curare-like action is little antagonized by neostigmine. From these facts, it was suggested that acetylcholine receptor was perhaps different from ChE.

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