Bis-azaaromatic quaternary ammonium salts as ligands for the blood-brain barrier choline transporter
12-diyl-bis-3-picolinium dibromide; analogs; Bis-quaternary ammonium salts; Blood-brain barrier; Chemistry; Choline transporter; evoked dopamine release; extracellular dopamine; hyperactivity; mediated transport; n; n'-dodecane-1; nicotinic-receptor antagonist; nucleus-accumbens; Pharmacology & Pharmacy; rat; tobacco dependence; vector
A series of bis-azaaromatic quaternary ammonium compounds containing flexible polymethylenic linkers as well as conformationally restricted linkers were evaluated for their affinity for the blood-brain barrier choline transporter (BBB-ChT). The preliminary structure-activity relationships obtained from this study suggest that incorporating a linear, conformationally restricted linker into the molecule improves affinity for the BBB-ChT. (C) 2010 Elsevier Ltd. All rights reserved.
Zheng G R; Zhang Z F; Lockman P R; Geldenhuys W J; Allen D D; Dwoskin L P; Crooks P A
Bioorganic & Medicinal Chemistry Letters
2010
2010-06
Journal Article
<a href="http://doi.org/10.1016/j.bmcl.2010.04.098" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2010.04.098</a>
N-Aryl-substituted 3-(beta-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy
4(1h)-pyridinone; biological evaluation; Blood-brain barrier; Chemistry; copper; Crystal structure; derivatives; disease; iron chelators; physicochemical properties; targeting a-beta; transgenic mice
Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimer's disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone(HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimer's brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(beta-Dglucopyranosyloxy)-1-[4-(4-[I-125] iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([I-125]-GL(7)) was shown to cross the blood-brain barrier using an in situ rat brain perfusion technique.
Scott L E; Telpoukhovskaia M; Rodriguez-Rodriguez C; Merkel M; Bowen M L; Page B D G; Green D E; Storr T; Thomas F; Allen D D; Lockman P R; Patrick B O; Adam M J; Orvig C
Chemical Science
2011
2011
Journal Article
<a href="http://doi.org/10.1039/c0sc00544d" target="_blank" rel="noreferrer noopener">10.1039/c0sc00544d</a>
Engineering triiodothyronine (T3) nanoparticle for use in ischemic brain stroke.
Blood-brain barrier; Brain stroke; Nanoparticles; Neuroprotection; Thyroid hormone
A potential means of pharmacological management of ischemic stroke is rapid intervention using potent neuroprotective agents. Thyroid hormone (T3) has been shown to protect against ischemic damage in middle cerebral artery occlusion (MCAO) model of ischemic brain stroke. While thyroid hormone is permeable across the blood-brain barrier, we hypothesized that efficacy of thyroid hormone in ischemic brain stroke can be enhanced by encapsulation in nanoparticulate delivery vehicles. We tested our hypothesis by generating poly-(lactide-co-glycolide)-polyethyleneglycol (PLGA-b-PEG) nanoparticles that are either coated with glutathione or are not coated. We have previously reported that glutathione coating of PLGA-PEG nanoparticles is an efficient means of brain targeted drug delivery. Encapsulation of T3 in PLGA-PEG delivery vehicle resulted in particles that were in the nano range and exhibited a zeta potential of -6.51 mV (uncoated) or -1.70 mV (coated). We observed that both glutathione-coated and uncoated nanoparticles are taken up in cells wherein they stimulated the expression of thyroid hormone response element driven reporter robustly. In MCAO model of ischemic stroke, significant benefit of administering T3 in nanoparticulate form was observed over injection of a T3 solution. A 34 % decrease in tissue infarction and a 59 % decrease in brain edema were seen upon administration of T3 solution in MCAO stroke model. Corresponding measurements for uncoated T3 nanoparticles were 51 % and 68 %, whereas for the glutathione coated were 58 % and 75 %. Our study demonstrates that using nanoparticle formulations can significantly improve the efficacy of neuroprotective drugs in ischemic brain stroke.
Mdzinarishvili Alexander; Sutariya Vijaykumar; Talasila Phani K; Geldenhuys Werner J; Sadana Prabodh
Drug delivery and translational research
2013
2013-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s13346-012-0117-8" target="_blank" rel="noreferrer noopener">10.1007/s13346-012-0117-8</a>