Introduction of unsaturation into theN-n-alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: Effect on affinity and selectivity
Journal Title: The AAPS Journal - Year 2005, Vol 7, Issue 1
Abstract
N-n-Octylnicotinium iodide (NONI) andN-n-decylnicotinium iodide (NDNI) are selective nicotinic receptor (nAChR) antagonists mediating nicotine-evoked striatal dopamine (DA) release, and inhibiting [3H]nicotine binding, respectively. This study evaluated effects of introducing unsaturation into theN-n-alkyl chains of NONI and NDNI on inhibition of [3H]nicotine and [3H]methyllycaconitine binding (α4β2* and α7* nAChRs, respectively),86Rb+ efflux and [3H]DA release (agonist or antagonist effects at α4β2* and α6β2*-containing nAChRs, respectively). In the NONI series, introduction of a C3-cis-(NONB3c), C3-trans-(NONB3t), C7-double-bond (NONB7e), or C3-triple-bond (NONB3y) afforded a 4-fold to 250-fold increased affinity for [3H]nicotine binding sites compared with NONI. NONB7e and NONB3y inhibited nicotine-evoked86Rb+ efflux, indicating α4β2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [3H]DA overflow compared with NONI (IC50=0.62 μM; Imax=89%), with no change in Imax, except for NONB3y (Imax=50%). In the NDNI series, introduction of a C4-cis-(NDNB4c), C4-trans-double-bond (NDNB4t), or C3-triple-bond (NDNB3y) afforded a 4-fold to 80-fold decreased affinity for [3H]nicotine binding sites compared with NDNI, whereas introduction of a C9-double-bond (NDNB9e) did not alter affinity. NDNB3y and NDNB4t inhibited nicotine-evoked86Rb+ efflux, indicating anatogonism at α4β2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [3H]DA overflow (IC50=0.02–0.14μM, Imax=90%), as did NDNB4c (IC50=0.08 μM; Imax=50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for α7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at α4β2*-and α6β2*-containing nAChRs, however a general reduction of affinity at α4β2* and an uncovering of antagonist effects at α6β2*-containing nAChRs were observed with unsaturated NDNI analogs.
Authors and Affiliations
Sangeetha P. Sumithran, Peter A. Crooks, Rui Xu, Jun Zhu, Agripina G. Deaciuc, Lincoln H. Wilkins, Linda P. Dwoskin
Keywords
Related Articles
- EP ID EP681865
- DOI 10.1208/aapsj070119
- Views 85
- Downloads 0
Brain natriuretic peptide: Potential adjunct for cardiac risk assessment and management during treatment with experimental anticancer agents
A pragmatic approach to the design of population pharmacokinetic studies
The publication of a seminal article on nonlinear mixed-effect modeling led to a revolution in pharmacokinetics (PKs) with the introduction of the population approach. Since then, interest in obtaining accurate and preci...
Nanoparticles Containing Anti-inflammatory Agents as Chemotherapy Adjuvants: Optimization and In Vitro Characterization
The pre-administration of dexamethasone (DEX) has previously been shown to enhance the anti-tumor efficacy of chemotherapeutic agents. The delivery of anti-inflammatory agents specifically to tumors via nanoparticle carr...
Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates
Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers
Chemoradiotherapy, the combination of chemotherapy and radiotherapy to treat cancer, has the potential to enhance local therapeutic effects and simultaneously treat systemic disease. However, chemoradiotherapy may also e...