525596-66-1Relevant articles and documents
3D-QSAR study of bis-azaaromatic quaternary ammonium analogs at the blood-brain barrier choline transporter
Geldenhuys, Werner J.,Lockman, Paul R.,Nguyen, Tiffany H.,Van Der Schyf, Cornelis J.,Crooks, Peter A.,Dwoskin, Linda P.,Allen, David D.
, p. 4253 - 4261 (2005)
Previously, we have developed 3D-QSAR models of the blood-brain barrier (BBB) choline transporter, a transport system that may have utility as a vector for central nervous system drug delivery. In this study, we extended the model by evaluating five bis-azaaromatic quaternary ammonium compounds for their affinity for the choline binding site on the BBB-choline transporter. The compounds, and their affinities for the transporter, were then incorporated into our existing molecular model, in order to update our knowledge on the molecular recognition factors associated with interaction of ligands at the choline binding site. The current compounds are structurally related to previous substrates that we have evaluated, but offer additional three dimensional aspects compared to the series of compounds previously utilized to define the original models. The compounds showed good affinity for the BBB-choline transporter, exhibiting inhibition constants ranging from 10 to 68 μM, as determined by the in situ rat brain perfusion method. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to build the new 3D QSAR models. When the new bis-azaaromatic quaternary ammonium compounds were included in the model, the best cross-validated CoMFA q2 was found to be 0.536 and the non-cross-validated r2 was 0.818. CoMSIA hydrophobic cross-validated q2 was 0.506 and the non-cross-validated r2 was 0.804. This new model was able to better predict BBB-choline transporter affinity of hemicholinium-3 (predicted 65 μM, actual 54 μM), when compared to an earlier model (predicted 316 μM).
BIS-PYRIDINO CONTAINING COMPOUNDS FOR USE IN THE TREATMENT OF CNS PATHOLOGIES
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Page/Page column 24, (2008/06/13)
N-n-Alkylation of nicotine converts nicotine from an agonist into an antagonist specifically for neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogs exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood-brain barrier choline transporter.
Subtype-selective nicotinic receptor antagonists: Potential as tobacco use cessation agents
Dwoskin, Linda P.,Sumithran, Sangeetha P.,Zhu, Jun,Deaciuc, A. Gabriela,Ayers, Joshua T.,Crooks, Peter A.
, p. 1863 - 1867 (2007/10/03)
N-n-Alkylpicolinium and N,N′-alkyl-bis-picolinium analogues were assessed in nicotinic receptor (nAChR) assays. The most potent and subtype-selective analogue, N,N′-dodecyl-bis-picolinium bromide (bPiDDB), inhibited nAChRs mediating nicotine-evoked [3H]dopamine release (IC50=5 nM; Imax of 60%), and did not interact with α4β2* or α7* nAChRs. bPiDDB represents the current lead compound for development as a tobacco use cessation agent.
bis-Azaaromatic quaternary ammonium analogues: Ligands for α4β2* and α7* subtypes of neuronal nicotinic receptors
Ayers, Joshua T.,Dwoskin, Linda P.,Deaciuc,Grinevich, Vladimir P.,Zhu, Jun,Crooks, Peter A.
, p. 3067 - 3071 (2007/10/03)
A series of bis-nicotinium, bis-pyridinium, bis-picolinium, bis-quinolinium and bis-isoquinolinium compounds was evaluated for their binding affinity at nicotinic acetylcholine receptors (nAChRs) using rat brain membranes. N,N′-Decane-1,12-diyl-bis-nicoti
