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. 2006 Jan 13;7(4):E922–E930. doi: 10.1208/aapsj070490

N-n-alkylnicotinium analogs, a novel class of antagonists at α4β2* Nicotinic acetylcholine receptors: Inhibition of S(-)-nicotine-evoked 86Rb+Efflux from rat thalamic synaptosomes

Lincoln H Wilkins 1, Dennis K Miller 3, Joshua T Ayers 4, Peter A Crooks 1, Linda P Dwoskin 1,✉
PMCID: PMC2750962  PMID: 16594645

Abstract

PyridineN-n-alkylation of S(-)-nicotine (NIC) affordsN-n-alkylnicotinium analogs, previously shown to competitively inhibit [3H]NIC binding and interact with α4β2* nicotinic receptors (nAChRs). The present study determined the ability of the analogs to inhibit NIC-evoked86Rb+ efflux from rat thalamic synaptosomes to assess functional interaction with α4β2* nAChRs. In a concentration-dependent manner, NIC evoked86Rb+ efflux (EC50=170 nmol/L). Analoginduced inhibition of NIC-evoked86Rb+ efflux varied over a ≈450-fold range. Analogs with longn-alkyl chain lengths (C9−C12) inhibited efflux in the low nmol/L range (IC50=9–20 nmol/L), similar to dihydro-β-erythroidine (IC50=19 nmol/L). Compounds with shortern-alkyl chain lengths (C1−C8) produced inhibition in the low μmol/L range (IC50 =3–12 μmol/L). C10 and C12 analogs completely inhibited NIC-evoked efflux, whereas C1–9 analogs produced maximal inhibition of only 10% to 60%. While the C10 analogN-n-decylnicotiniumiodide (NDNI) did not produce significant inhibition of NIC-evoked dopamine release in previously reported studies, NDNI possesses high affinity for [3H]NIC binding sites (Ki=90 nmol/L) and is a potent and efficacious inhibitor of NIC-evoked86Rb+ efflux as demonstrated in the current studies. Thus, NDNI is a competitive, selective antagonist at α4β2* nAChRs.

Keywords: nicotine analogs, subtype-selectivity, neuronal nicotinic receptor

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