Chemical Nature and Pharmacological Actions of Quaternary Ammonium Salts

Neuromuscular Blocking Properties of Stereoisomeric Androstane‐3, 17‐bisquaternary Ammonium Salts

“…If we consider that the most potent stereoisomers were always the 3,8-bisquaternary members of each series, that change in this configuration causes a loss of potency of two to eleven times, and further that configurational change at the 17-position does not significantly affect potency, then one might postulate that interaction with the receptor at the 3-position is more important than interaction in either configuration at the 17-position. Thus our results would tend to support the adumbration theory of Loewe & Harvey (1952), who postulated a "one point" attachment theory, where the bulk of the molecule, in this case presumably the steroid nucleus, shields the receptor, rather than the suggestion of Cavallito &Gray (1960), andWaser (1959), that a two point receptor complex could be formed. The relatively flat steroid nucleus in the 5a-series may be a more effective shield than the more folded steroid nucleus of the 5/3-series, and therefore the 5a-series should be more potent than the corresponding members of the 5/3-series, which accords with our observations.…”

Antihypertensive Agents

“…Extensive studies by RICE [16] and CA v ALLITO [ 17] revealed surprisingly different structural-activity requirements in asymmetrical bis-ammonium compounds (Table 3). A voluminous, lipophilic-substituted cationic substituent A linked by a <::2 or C 3 chain to a compact ammonium group C appears to be the optimal structure requirement for sympathetic ganglionic blockade.…”

“…++++ [20] ©O $ N(CH3h +++ [17] Because most of the early ganglionic blockers were quarternary ammonium salts, major efforts were concentrated on the synthesis of these compounds which were more potent than the parent tertiary amines. Interest in the latter group of compounds was generated by the observation by MIZZONI et al [21] that tertiary amines, like nicotine, have a similar potential to interact with ganglionic transmission.…”

Non-depolarising neuromuscular blockade by 3α,17α-bis(quaternary ammonium) 5α-androstanes

“…Non-depolarising neuromuscular blockade by 3a, 17a-bis(quaternary ammonium) 5a-androstanes SIR,-Although many molecular features are known to influence neuromuscular blocking activity and plausible alternative explanations exist (Loewe & Harvey, 1952;Cavallito & Gray, 1960;Waser, 1959Waser, , 1962, the potent neuromuscular blocking activity characteristic of certain bisquaternary salts is often envisaged in terms of a "two-point" attachment in which the cationic heads interact simultaneously with separate anionic sites of the acetylcholine receptors on the post-synaptic membrane as first proposed by Rarlow & Ing (1948a, b) and Paton & Zaimis (1948, 1949.…”

“…Our assumption that such compounds would possess a suitable hydrophilic to lipophilic balance-known to be of importance in neuromuscular blocking activity (Cavallito & Gray, 1960)was subsequently borne out by the observation that the steroidal alkaloid malouetine possessed activity similar to that shown by (+)-tubocurarine (Janot & others, 1960). The compounds so prepared were then to be used for an investigation of the importance of interonium distance and cationic head size in neuromuscular blocking activity.…”