Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found in the central and peripheral nervous systems. They regulate neurotransmitter release throughout the CNS and facilitate fast synaptic transmission. nAChRs have been implicated in autism, depression, schizophrenia, and nicotine addiction, although not many medications targeting the cholinergic system are available. Positive allosteric modulation is a developing method of pharmacological treatment. Des-formyflustrabromine (dFBr), is a positive allosteric modulator (PAM) of α4β2 nicotinic acetylcholine receptors. Galantamine is both and acetylcholinesterase inhibitor (AChEI) and a PAM that is used in the treatment of Alzheimer’s disease (AD).
Using two-electrode voltage clamp electrophysiology (TEVC), we investigated the selectivity of dFBr with a series of heteromeric nicotinc receptors. We found that dFBr does not potentiate α3β4, α3β2, or α4β4 receptors. In addition, our results indicate that both α4 and β2 receptors contribute to the potentiation by dFBr seen in α4β2 receptors.
Based on established interactions between ethanol and the cholinergic system, we hypothesized that dFBr will affect ethanol-induced loss of righting reflex (LORR) as well as nicotinic receptor subunit protein expression. In vivo experiments in Sprague Dawley rats demonstrated that dFBr reduces the LORR duration caused by ethanol and reduces the ethanol-induced increase in α4 protein expression in the thalamus.
The results for galantamine question its established function as an allosteric modulator. It was found that galantamine does not potentiate currents elicited by acetylcholine. A structure activity relationship (SAR) study of galantamine found that some analogs induce inhibition of the ACh response of the nicotinic receptor while others have no effect.
|Commitee:||Schulte, Marvin, Harvison, Peter, Koo, Yumee|
|School:||University of the Sciences in Philadelphia|
|Department:||Pharmacology & Toxicology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/11(E), Dissertation Abstracts International|
|Keywords:||Nicotinic acetylcholine receptors|
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