A series of bis-nicotinium, bis-pyridinium, bis-picolinium, bis-quinolinium and bis-isoquinolinium compounds was evaluated for their binding affinity at nicotinic acetylcholine receptors (nAChRs) using rat brain membranes. N,N′-Decane-1,12-diyl-bis-nicotinium diiodide (bNDI) exhibited the highest affinity for [3H]nicotine binding sites (Ki=330 nM), but did not inhibit [3H]methyllycaconitine binding (Ki > 100 μM), indicative of an interaction with α4β2*, but not α7* receptor subtypes, respectively. Also, bNDI inhibited (IC50=3.76 μM) nicotine-evoked 86Rb+ efflux from rat thalamic synaptosomes, indicating antagonist activity at α4β2* nAChRs. N,N′-Dodecane-1,12-diyl-bis-quinolinium dibromide (bQDDB) exhibited highest affinity for [3H]methyllycaconitine binding sites (Ki=1.61 μM), but did not inhibit [3H]nicotine binding (Ki > 100 μM), demonstrating an interaction with α7*, but not α4β2* nAChRs. Thus, variation of N-n-alkyl chain length together with structural modification of the azaaromatic quaternary ammonium moiety afforded selective antagonists for the α4β2* nAChR subtype, as well as ligands with selectivity at α7* nAChRs.
|Number of pages||5|
|Journal||Bioorganic and Medicinal Chemistry Letters|
|State||Published - Nov 4 2002|
Bibliographical noteFunding Information:
This work was supported by grants from the National Institute on Drug Abuse (DA10934, DA00399).
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry