AN EVALUATION OF THE FACTORS FAVORABLE FOR ACETYL-CHOLINE-LIKE STIMULATION BY EMPLOYING A SERIES OF QUATERNARY AMMONIUM ALKYL SULFIDE AND SULFOXIDE COMPOUNDS

¹ Pharmacology Section and Organic Chemistry Division, Sterling-Winthrop Research Institute, Rensselaer, New York

1. The effect of molecular configuration on acetylcholine-sensitive structures in various visceral organs, sympathetic ganglia and at the motor end-plate of skeletal muscle has been investigated by means of 3-(methylmercapto) propyl-trimethylammonium iodide and by various analogs of this molecule wherein the effect of modification of the structure of the ammonium nitrogen center as well as the structure of the appendage group has been determined.

2. The above receptor mechanisms demonstrate a high degree of specificity in their affinity for the synthetic compounds used in this investigation. Each type of receptor is optimally influenced by compounds which are less than optimally effective at the other receptor sites.

3. The parasympathetic (muscarine-sensitive) end-organs are most readily stimulated by synthetic alkylammoniums in which the cationic head is small and where the appendage structure has an overall length of approximately 7.5 Å. A nucleophilic group, such as a sulfur atom introduced between the third and fourth carbon atoms of the appendage structure, enhances stimulating activity.

4. Stimulation of sympathetic ganglia is favored by trimethylammoniums in which the length of the appendage structure is 9 Å. The presence of a nucleophilic group does not enhance stimulating activity in the examples tested.

5. Depolarizing (C-10) type of muscular paralysis is obtained most readily with trimethylammoniums in which the length of the appendage structure is 7.5 Å. The presence of a nucleophilic structure 4.5-5.0 Å from the nitrogen center favors this action.

6. The presence of a sulfoxide or sulfonium group in the appendage structure greatly reduces stimulating action at all of the above named sites.

7. Replacement of the methyl groups of the cationic head by larger alkyl groups reduces stimulating action and, in the case of the motor end-plate, may alter the character of the action from depolarizing or C-10 type to a curare-like paralysis.

8. Structural configurations of the thio derivatives described here were not favorable for attachment to acetylcholinesterase, as determined by the inhibition of acetylcholine hydrolysis.