Novel Nicotinic Acetylcholine Receptor Inhibitors Derived from Oleoylcholine Analogs

Area of Science:

• Biochemistry
• Neuroscience
• Pharmacology

Background:

• Fatty acid-acylated cholines are endogenous compounds modulating the cholinergic system.
• Acylcholines function as cationic lipids for nucleic acid delivery.
• Previous work established acylcholines' role in modulating cholinergic systems.

Purpose of the Study:

• To investigate the interaction of ionic forms of oleoylcholine (Ol-Chol) and synthetic cationic lipids with nicotinic acetylcholine receptors (nAChR).
• To compare the binding affinities and functional effects of these compounds on muscle-type and α7 nAChR.
• To elucidate the mechanisms underlying their inhibitory and cytotoxic activities.

Main Methods:

• Radioligand binding assays to determine binding affinity to muscle-type and α7 nAChR.
• Functional calcium imaging assays to assess nAChR inhibition.
• Cytotoxicity assays on SH-SY5Y neuroblastoma cells.

Main Results:

• Acylcholines and synthetic lipids showed higher affinity for muscle-type nAChR than for human neuronal α7 nAChR (2-5.5 fold).
• Oleoylcholine iodide exhibited higher binding efficacy than its mesylate form.
• Both compound types potently inhibited α7 nAChR, suggesting allosteric site interactions.
• Synthetic lipids had reduced α7 nAChR binding efficacy but induced significant cytotoxicity independent of nAChR.
• Cytotoxicity was linked to the quaternary ammonium group and lipophilic moiety modifications.

Conclusions:

• The quaternary ammonium group is responsible for nAChR inhibition.
• Lipophilic modification with oleic acid residues reduces nAChR inhibitory properties.
• Lipophilic modifications enhance cytotoxicity through a mechanism independent of nAChR.