Curare-like Action of Polymethylene bis-Quaternary Ammonium Salts

Abstract

Tubocurarine chloride was shown by King (1935King ( , 1936 to be a bis-tetrahydroisoquinolinium salt containing two quaternary nitrogen atoms. The curare-like blocking of neuromuscular transmission is a property of " onium cations " in general, and it was thought that the exceptional potency of tubocurarine compared with shnple quaternary ammonium ions might be due in part to the presence of two such cationic groups at some optimal distance apart in the same molecule. With this in mind we have prepared and tested for curare-like activity a number of simple bisquaternary ammonium salts in which the nitrogen atoms were directly attached to the terminal carbon atoms of polymethylene chains of different lengths. Such salts may be conveniently referred to as " bis-onium salts " ; they were all polymethylene bis-onium dibromides of the general type :Few compounds of this type have been examined previously ; Brieger (1886) observed that tetramethylene bis-trimethylammonium hydroxide had some curare-like action in intact animals, and Ackermann (1921) made similar observations with the analogous ethylene and pentamethylene bistrimethylammonium aurichlorides.The following salts have been investigated. 1.Bis-trimethylammonium dibromides, Br{Me,N(CHJ,,NMe,}Br, where n was 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, and 13. They are referred to as BTM followed by the number (n) of methylene groups in the chain; thus trimethylene bis-trimethylammonium dibromide is referred to as BTM3.Br(Et,N(CH,),,NEt,}Br, where n was 2, 3, 4, 5, 7, 8, 9, 10, and 13. They are referred to as BTEn. 2.Bis-triethylammonium dibromides, 3. Bis-strychninium dibromides, Br{C~~HaaO~N~(CH~)nC~~Ha~OaN~}~jT, where n was 2,3, and 5. They are referred to as BSn.Br{C,H7N(CHa),CsH,N}Br, where n was 3, 5, and 10. They are referred to as BQn. 5.Bis-(phenyldimethylaonium) dibromides, Br{PhMenN(CHa),,NMeaPh}Br, where n was 3 and 5. They are referred to as BPDMn.The following abbreviations will also be used : TM for tetramethylammonium iodide and T E for tetra-ethylammonium iodide A brief note on some of the results with these bis-onium salts has already appeared (Barlow and Ing, 1948). Bis-quinolinium dibromides, METHODThe choice of a method for comparing the curarelike activity of numerous compounds is a matter of some difficulty ; older methods have been reviewed by Ing (1936). Recently two methods have been devised for assaying tubocurarine solutions : Holaday (quoted by Bennett, 1941) developed the rabbit headdrop method and Chou (1947) used the isolated phrenic nerve-diaphragm preparation of the rat. We have tried to adapt Chou's method to the comparison of the curare-like activities of our bis-onium salts. Initially the apparatus and procedure were exactly the same as those used by Chou, except that the bath was smaller (50 ml. instead of 100 ml.). The condenser discharge stimuli used by Chou were of about 100 duration and as there was a tendency for the nerve to discharge more than once they were later replaced by square wave stimuli of about 0.10 duration. It wa...

Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis.

“…Bisquaternary ligands, such as decamethonium (33), are more potent inhibitors of AcChoEase than the corresponding monoquaternary ligands; this has been ascribed to their binding simultaneously to the anionic subsite of the catalytic site and to the "peripheral" anionic site (6). Binding studies of several series of n-alkyl bisammonium ions (34,35) have shown an optimal separation of 14-15 A between the two quaternary groups, whereas the distance between the two indole moieties of Trp-84 and Trp-279 is 16 A in AcChoEase. These data can be rationalized by assuming that Trp-279, at the mouth of the active-site gorge, is an important component ofthe peripheral anionic site.…”

NMR Study of ganglion‐blocking and curare‐like dimethoniums conformation in aqueous solutions

“…(CH,), 1;-(CH,),-1; (CHs)s, 2 XIt is a well known fact that the biological activity of these bications varies with "n" [5]. From these findings several authors have attempted to relate the activity to the cation structure [6,7].…”

Curare‐like Action of Polymethylene Bis‐quaternary Ammonium Salts

“…They are referred to as BTEn. The following abbreviations will also be used: TM for tetramethylammonium iodide and TE for tetra-ethylammonium iodide A brief note on some of the results with these bis-onium salts has already appeared (Barlow and Ing, 1948). …”