Cholinergic false transmitters: physiological and biochemical actions in central and peripheral systems

Area of Science:

• Pharmacology
• Neuroscience
• Medicinal Chemistry

Background:

• Cholinergic transmission is vital for numerous physiological processes.
• False neurotransmitters offer a strategy to modulate neurotransmission.
• Understanding structure-activity relationships of acetylcholine analogs is key.

Purpose of the Study:

• To evaluate N-ethyl substituted acetylcholine analogs as potential false neurotransmitters.
• To assess their effects on central and peripheral cholinergic systems.
• To determine their interactions with muscarinic and nicotinic receptors.

Main Methods:

• Central administration to measure arterial blood pressure elevation.
• Intravenous injection to assess blood pressure depression.
• Receptor binding assays for central muscarinic and peripheral nicotinic receptors.

Main Results:

• Acetylcholine (ACh), acetylmonoethylcholine (AMECh), and acetyldiethylcholine (ADECh) exhibited varying agonist potencies and durations for central pressor responses.
• ADECh and acetyltriethylcholine (ATECh) were significantly weaker partial agonists for peripheral depressor responses compared to ACh and AMECh.
• Receptor binding affinities varied, with ACh and AMECh showing higher affinity for both muscarinic and nicotinic receptors, and interacting with multiple conformations.

Conclusions:

• AMECh and ADECh demonstrate potential as false neurotransmitters with differential effects on cholinergic transmission.
• ATECh exhibits limited agonist activity and receptor affinity, suggesting it is not a suitable false neurotransmitter.
• The N-ethyl substitution pattern significantly influences the pharmacological profile and receptor interactions of acetylcholine analogs.