Action of some bisquaternary derivatives of phthalic acids and related substances on neuromuscular transmission.
1. All the bisquaternary derivatives of terephthalic acid with three methyl groups on each nitrogen atom (PK-107, PK-95, PK-97 and PK-126) were depolarizing neuromuscular blocking agents. The most active was the compound PK-97, in which the two quaternary groups are separated by sixteen atoms and are about 20 A (2 nm) apart. Activity was reduced many fold either by decreasing the separation to twelve atoms or by increasing it to eighteen atoms. It was also reduced several hundred fold when one trimethylammonium group in PK-97 was replaced by a hydrogen atom (as in PK-119).2. The presence and position of the ester groups in these compounds is important; depolarizing activity is in most cases greatest when the ester groups are the same distance from the quaternary nitrogen atoms as in acetylcholine, that is, in carbolonium, sebacoyldicholine and PK-154. The monoquaternary analogues of carbolonium and sebacoyldicholine are appreciably active, having between about one-tenth to one-fifth of the activity of their bisquaternary analogues.3. The relationships between the structure and activity of these compounds are discussed, particular consideration being given to the structure of the chain separating the quaternary groups and the arrangement of acetylcholine receptors on cells and of esterbinding groups within these receptors.
D000109:Acetylcholine; D000818:Animals; D001001:Anura; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects; D004952:Esters; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009132:Muscles / Q000187:drug effects; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects*; D009584:Nitrogen; D010795:Phthalic Acids / Q000494:pharmacology*; D051381:Rats; D011950:Receptors, Cholinergic; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D004952:Esters; D009467:Neuromuscular Depolarizing Agents; D010795:Phthalic Acids; D011950:Receptors, Cholinergic; D009584:Nitrogen; D000109:Acetylcholine