244025-06-7Relevant articles and documents
N-n-alkylnicotinium analogs, a novel class of nicotinic receptor antagonists: Interaction with α4β2* and α7* Neuronal nicotinic receptors
Wilkins Jr., Lincoln H.,Grinevich, Vladimir P.,Ayers, Joshua T.,Crooks, Peter A.,Dwoskin, Linda P.
, p. 400 - 410 (2003)
The current study demonstrates that N-n-alkylnicotinium analogs with increasing n-alkyl chain lengths from 1 to 12 carbons have varying affinity (Ki = 90 nM-20 μM) for S-(-)-[3H]nicotine binding sites in rat striatal membranes. A linear relationship was observed such that increasing n-alkyl chain length provided increased affinity for the α4β2* nicotinic acetylcholine receptor (nAChR) subtype, with the exception of N-n-octylnicotinium iodide (NONI). The most potent analog was N-n-decylnicotinium iodide (NDNI; Ki = 90 nM). In contrast, none of the analogs in this series exhibited high affinity for the [3H]methyllycaconitine binding site, thus indicating low affinity for the α7* nAChR. The C8 analog, NONI, had low affinity for S-(-)-[3H]nicotine binding sites but was a potent inhibitor of S-(-)-nicotine-evoked [3H]dopamine (DA) overflow from superfused striatal slices (IC50 = 0.62 μM), thereby demonstrating selectivity for the nAChR subtype mediating S-(-)-nicotine-evoked [3H]DA overflow (α3α6β2* nAChRs). Importantly, the N-n-alkylnicotinium analog with highest affinity for the α4β2* subtype, NDNI, lacked the ability to inhibit S-(-)-nicotine-evoked [3H]DA overflow and, thus, appears to be selective for α4β2* nAChRs. Furthermore, the present study demonstrates that the interaction of these analogs with the α4β2* subtype is via a competitive mechanism. Thus, selectivity for the α4β2* subtype combined with competitive interaction with the S-(-)-nicotine binding site indicates that NDNI is an excellent candidate for studying the structural topography of α4β2* agonist recognition binding sites, for identifying the antagonist pharmacophore on the α4β2* nAChR, and for defining the role of this subtype in physiological function and pathological disease states.
Bifunctional compounds targeting both D2and non-α7 nACh receptors: Design, synthesis and pharmacological characterization
Matera, Carlo,Pucci, Luca,Fiorentini, Chiara,Fucile, Sergio,Missale, Cristina,Grazioso, Giovanni,Clementi, Francesco,Zoli, Michele,De Amici, Marco,Gotti, Cecilia,Dallanoce, Clelia
, p. 367 - 383 (2015)
We designed, prepared and tested a set of structural analogs 1-4 as new hybrid compounds by incorporating, through a common alkyl chain of variable length, the pharmacophoric elements of N-n-alkyl nicotinium salts (non-α7 nicotinic acetylcholine receptors antagonists) and of 7-hydroxy-2-(aminomethyl)chromanes (dopaminergic D2receptor agonists). The target compounds, which were assayed in binding experiments and electrophysiological, functional and Erk1/2 activation tests, essentially combined the pharmacological profiles of their individual receptor ligands. Among the studied derivatives, hybrid 2, one of the shortest homologs, in addition to the antagonist nicotinic profile similar to the other three congeners, behaved as a high affinity ligand at the investigated heteromeric nAChRs and as a low efficacy agonist at D2Rs. These bifunctional derivatives represent novel pharmacological tools in the study of nicotine addiction.
