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

Pyridine N-n-alkylation of S(-)-nicotine (NIC) affords N-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-evoked ⁸⁶Rb⁺ efflux from rat thalamic synaptosomes to assess functional interaction with α4β2^* nAChRs. In a concentration-dependent manner, NIC evoked ⁸⁶Rb⁺ efflux (EC₅₀ + 170 nmol/L). Analog-induced inhibition of NIC-evoked ⁸⁶Rb⁺ efflux varied over a ∼450-fold range. Analogs with long n-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 shorter n-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 C_1-9 analogs produced maximal inhibition of only 10% to 60%. While the C₁₀ analog N-n-decylnicotinium iodide (NDNI) did not produce significant inhibition of NIC-evoked dopamine release in previously reported studies, NDNI possesses high affinity for [³H]NIC binding sites (K_i = 90 nmol/L) and is a potent and efficacious inhibitor of NIC-evoked ⁸⁶Rb⁺ efflux as demonstrated in the current studies. Thus, NDNI is a competitive, selective antagonist at α4β2* nAChRs.