Neuroscience 2005 Abstract
| Presentation Number: | 951.5 |
|---|---|
| Abstract Title: | Functional properties of nicotine analogs acting upon α4β2 nicotinic acetylcholine receptors. |
| Authors: |
Wildeboer, K. M.*1
; Soti, F.1
; Kem, W. R.1
1Dept Pharmacology and Therapeutics, Univ. of Florida, Gainesville, FL |
| Primary Theme and Topics |
Neural Excitability, Synapses, and Glia: Cellular Mechanisms - Ligand-Gated Ion Channels -- Nicotinic acelylcholine receptors: Physiology |
| Secondary Theme and Topics | Disorders of the Nervous System<br />- Addiction and Drugs of Abuse<br />-- Nicotine |
| Session: |
951. Nicotinic Acetylcholine Receptors: Physiology I Poster |
| Presentation Time: | Wednesday, November 16, 2005 1:00 PM-2:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # D49 |
| Keywords: | Nicotinic Receptor, Nicotine, Acetylcholine, Drug |
Neuronal α4β2 nicotinic cholinergic receptors are the major high affinity nAChRs in the mammalian brain and mediate much of the dopamine releasing and cognition-enhancing effects of nicotine in the brain. Although many nicotine analogs have been synthesized and their α4β2 nAChR affinities measured by various labs, the functional properties of many of these compoundswere not investigated. We previously reported the binding affinities of several nicotine analogs for both rat α4*β2 and α7 nAChRs (Wildeboer et al., 2003, SFN Mtg Abstr. 158.6). Here we report the functional properties of these same analogs when tested on the human α4β2 nAChR. Membrane depolarizing effects on tsA201 cells (provided by J. Lindstrom, U. Penn.) were measured using a Molecular Devices fluorescent dye. The signals were normalized using a KCl calibrant and responses were expressed relative to the maximal response produced by nicotine. The maximal responses of all compounds including nicotine were always much smaller than the KCl depolarizing response, indicating a lack of spare receptors. Although increasing the steric bulk of the pyrrolidinyl N-alkyl group from methyl to ethyl, propyl or methylcyclopropyl greatly reduces binding affinity, all three analogs were strong partial agonists in the functional assay. All three pyrrolidine C-methylated nicotine analogs (racemic 3’-trans-methyl-nicotine, 5’-cis-methyl-nicotine and 5’-trans-methyl-nicotine) were very weak partial agonists. The 5’-trans-methyl-(S)-nicotine was previously reported to inhibit nicotine self administration in rats (Rowland et al., 2003, SFN Mtg Abstr. 247.14). Finally, racemic 5-phenyl- and 5-(3-pyridyl)-nicotines were antagonists at the human α4β2 receptor. An emerging SAR may permit design of more selective α4β2 ligands, both agonists and antagonists, for probing the functional roles of this nAChR subtype. (Supported by NIH RO1 MH6142 and Florida Sea Grant R/LR-MB-20).
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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