Abstract

1. Thirty-eight synthetic compounds, all of them esters of disubstituted acetic acids, have been tested for anticholinergic activity against acetylcholine-stimulated ileal strips. One of them (158) proved superior to, and two of them (154, 96) proved equal to atropine in activity. The quaternary alkamines were generally more potent than their corresponding tertiary alkamines. Two compounds (79, 95) also exhibited significant antispasmodic action against barium chloride induced contractures in vitro.

2. Five of the more active compounds were tested in the cat for atropine-like action on the intact intestines, and on salivary flow in the rabbit. One compound (158), whose spasmolytic effects were superior to atropine both in vitro and in vivo, exhibited ¾ of the inhibitory effect of atropine on salivary secretion.

3. Eight compounds were tested for anticholinergic activity on blood pressure.

4. The paralellism between the antagonism of drugs to nicotine-induced tremors and the satisfactory clinical use of these drugs in the alleviation of Parkinson's symptomatology has been discussed. Compound 93 afforded complete protection against nicotine-induced tremors on intravenous administration, and partial protection by oral administration.

5. The toxicity of the compounds was presented in comparison with presently used antispasmodic agents. In general, the quaternary methosalts were approximately four times as toxic as the tertiary amines. Chronic toxicity studies gave no indication of any pathological changes in essential organs.

6. Mydriatic activity was tested in rabbits. The quaternary methohalides caused incomplete mydriasis in all cases tried. The tertiary compounds proved to be satisfactory mydriatics, in the laboratory, and are now undergoing clinical trial.

7. The relationship between chemical structure and pharmacological activity has been discussed.