5.12:
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists bind to AChE enzymes at the synaptic cleft and inhibit ACh hydrolysis. This results in increased concentration of ACh at the synapse, indirectly enhancing cholinergic action.
In general, they are classified as either reversible or irreversible inhibitors based on their duration of action.
Reversible inhibitors are short- and intermediate-acting agents.
Short‐acting agents are simple alcohols bearing quaternary ammonium groups such as edrophonium.
Intermediate‐acting agents include carbamic esters such as neostigmine and physostigmine.
Neostigmine is a carbamate bearing a quaternary ammonium group, while physostigmine is a naturally occurring carbamate with a tertiary amine group.
Irreversible inhibitors include organophosphates. They are phosphoric acid derivatives with multiple substituents, where one of the substituents functions as a labile group.
For instance, echothiophate consists of two alkoxy groups and one thiocholine group. Sarin, a nerve gas, has one alkoxy, one alkyl, and one halogen group. Here, the thiocholine and halogen are labile groups.
5.12:
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with quaternary ammonium groups, such as edrophonium. Intermediate-acting agents possess medium durations of action and are carbamic acid esters containing tertiary or quaternary ammonium groups. Physostigmine, a natural carbamate, features a tertiary amine group, while neostigmine, a synthetic carbamic ester, has a quaternary ammonium group.
Reversible inhibitors display short and medium durations of action. Short-acting agents include simple alcohols with quaternary ammonium groups, such as edrophonium. Intermediate-acting agents possess medium durations of action and are carbamic acid esters containing tertiary or quaternary ammonium groups. Physostigmine, a natural carbamate, features a tertiary amine group, while neostigmine, a synthetic carbamic ester, has a quaternary ammonium group.
Irreversible inhibitors are phosphoric acid derivatives with multiple substituents, where one substituent serves as a labile group. Echothiophate, for instance, comprises two alkoxy groups and one labile thiocholine group. Similarly, sarin, a toxic nerve gas, contains one alkoxy group, one alkyl group, and a labile halogen group.