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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

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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.

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Author notes

  1. Lincoln H. Wilkins

    Present address: Bristol-Myers Squibb Co, 309 Dove Park Road, 70433, Covington, LA

Authors and Affiliations

  1. College of Pharmacy, University of Kentucky, 40536-0082, Lexington, KY

    Lincoln H. Wilkins, Peter A. Crooks & Linda P. Dwoskin

  2. Department of Psychological Services, University of Missouri, 208 McAlester Hall, 65211, Columbia, MO

    Dennis K. Miller

  3. AstraZeneca, 1800 Concord Pike, PO Box 15437, 19850-5437, Wilmington, DE

    Joshua T. Ayers

Authors
  1. Lincoln H. Wilkins
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  2. Dennis K. Miller
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  3. Joshua T. Ayers
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  4. Peter A. Crooks
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  5. Linda P. Dwoskin
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Correspondence to Linda P. Dwoskin.

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Published: January 13, 2006

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Wilkins, L.H., Miller, D.K., Ayers, J.T. et al. 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. AAPS J 7, 90 (2005). https://doi.org/10.1208/aapsj070490

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  • DOI: https://doi.org/10.1208/aapsj070490

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