24 Questions
What is the primary concern for oral administration of ACh?
Acid/base catalyzed hydrolysis
What is the optimal size of the alkyl group substituted on the nitrogen for maximum potency?
Methyl group
Which of the following modifications would improve water solubility of ACh?
Adding a hydrophilic group
What is the consequence of having more than one large alkyl group on the nitrogen?
Decreased potency
What is the primary function of the quaternary ammonium group in ACh?
Providing optimal functional moiety for activity
Which of the following compounds is an exception to the optimal quaternary ammonium group SAR?
Pilocarpine
What is the product of acid/base catalyzed hydrolysis of ACh?
Acetic acid and choline
Why is the trimethylammonium group optimal for activity?
It provides optimal interactions with the receptor
What happens when nitrogen atom is replaced by arsenic, phosphorus, or sulfur in cholinergic compounds?
They become less active clinically
What is the effect of substituents of larger size than methyl groups on activity?
Decreased activity
What is the role of the ester group in ACh?
It forms hydrogen bonds with receptor sites
What is the effect of replacing methyl with amine group in choline esters?
It becomes less readily hydrolyzed by gastric acid
What is the muscarinic selectivity of acetyl‐β‐methylcholine (methacholine) compared to acetylcholine?
Greater muscarinic selectivity
What is the effect of adding methyl groups to either one or both of the ethylene carbons in cholinergic compounds?
It results in chiral molecules
What is the advantage of carbamate (carbachol) over ester group in terms of oral administration?
It is less readily hydrolyzed by gastric acid
What is the characteristic of choline esters of aromatic or higher‐molecular‐weight acids?
Cholinergic antagonist activity
What is the primary characteristic of nicotinic receptors in the classification of cholinergic receptors?
Ability to bind to nicotine
What is the purpose of cholinergic receptor agonists in pharmacology?
To mimic the action of acetylcholine
What is a crucial structural requirement for a molecule to possess muscarinic activity?
A two-carbon unit between the oxygen and nitrogen atoms
Why do quaternary ammonium groups improve the selectivity of muscarinic receptors?
They provide a positive charge, allowing for selective binding to muscarinic receptors
What is a potential issue with oral administration of cholinergic agonists?
Instability in the presence of esterases
What is the purpose of modifying the ester group in cholinergic agonists?
To enhance the molecule's oral stability
What is a characteristic of cholinergic antagonists?
They block the action of acetylcholine
What is the significance of the oxygen atom in the structure-activity relationship of acetylcholine?
It is capable of participating in a hydrogen bond
Study Notes
Structure-Activity Relationship (SAR) of Acetylcholine
- Acetylcholine (ACh) is easily hydrolyzed by acid in the Gastrointestinal Tract (GIT) and by pseudocholinesterase.
- For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group.
- Two methyl groups on the nitrogen are required, and a larger third alkyl group is tolerated, but more than one large alkyl group leads to loss of activity.
- The quaternary ammonium group is the optimal functional moiety for activity.
Modification of the Quaternary Ammonium Group
- Replacing the nitrogen atom with arsenic, phosphorus, or sulfur results in less active compounds and are not used clinically.
- Substituents of larger size than methyl groups also result in decreased activity or sometimes, antagonist activity (e.g., ethyl group).
Modification of the Ester (Acyloxy) Group
- The ester group in ACh forms a hydrogen bond with threonine and asparagine residues at receptor sites.
- Choline esters of aromatic or higher molecular weight acids possess cholinergic antagonist activity.
- Replacing the methyl with an amine group results in a carbamate (carbachol), which is more resistant to hydrolysis than the ester group.
Modification of the Ethylene Bridge
- Methyl substitution affords acetyl-β-methylcholine (methacholine), which has muscarinic potency almost equivalent to that of ACh and much greater muscarinic than nicotinic selectivity.
- Addition of methyl groups to either one or both of the ethylene carbons results in chiral molecules.
Cholinergic Receptors
- Classification of cholinergic receptors based on their ability to bind to either nicotine or muscarine.
- Nicotinic receptors and muscarinic receptors have distinct subtypes.
Cholinergic Agonists
- Drugs that mimic ACh by direct acting on cholinergic receptors in tissues or block the action of AChE.
- The molecule should have an oxygen atom, preferably an ester-like oxygen capable of participating in a hydrogen bond.
- A two-carbon unit should occur between the oxygen atom and the nitrogen atom.
- A molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt.
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