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 C1-9 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 (Ki = 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.
|State||Published - Jan 13 2006|
Bibliographical noteFunding Information:
This study was supported by National Institutes of Health (NIH) Grants DA00399, DA06043, DA10934, and DA17548. The authors express gratitude to Dr James R. Pauly for technical support in the performance of this research.
- Neuronal nicotinic receptor
- Nicotine analogs
ASJC Scopus subject areas
- Pharmaceutical Science