5.13: Indirect-Acting Cholinergic Agonists: Mechanism of Action

Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.

Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to a short duration of action.

Other reversible inhibitors, such as carbamic acid esters, bind to a different part of the enzyme called the esteratic site. They replace a specific group on the enzyme with their carbamyl group. This creates a carbamoylated enzyme, which undergoes slow hydrolysis over several minutes. As a result, these inhibitors have a longer duration of action.

Irreversible inhibitors, such as organophosphates, also bind to the esteratic site of the enzyme. However, they form covalent bonds, which are strong and permanent. These inhibitors phosphorylate a specific group on the serine hydroxyl enzyme, creating an irreversible enzyme–inhibitor complex that lasts for a long time.

The stability of the irreversible enzyme–inhibitor complex can be further enhanced through a process called aging. During aging, one of the bonds between oxygen and phosphorus in the inhibitor breaks, making the phosphorus–enzyme bond even stronger.

Recall that indirect-acting cholinergic agonists inhibit AChE enzymes. This prevents hydrolysis of acetylcholine in the synapse and potentiates cholinergic activity at post-synaptic neurons or neuromuscular junctions.

The active site of the enzyme has a choline-binding anionic and a catalytic esteratic subsite.

Reversible inhibitors such as simple alcohols bearing quaternary ammonium groups interact electrostatically with the enzyme. As the enzyme–inhibitor complex is less stable and reversible, such agents have a brief duration of action.

Reversible inhibitors that are carbamoyl esters transfer their carbamoyl group to the serine hydroxyl group of the esteratic subsite. As the carbamoylated enzyme is more stable and undergoes slow hydrolysis, these drugs have a medium duration of action.

Organophosphates, however, interact covalently and phosphorylate the serine residue. This forms an irreversible complex resulting in a long-lasting effect of the drug.

The phosphorylated enzyme's stability is enhanced through the process called aging. Here, one of the alkyl group is lost which further strengthens the phosphorus–enzyme bond.