University of California

The Scripps Research Institute

Other

Oak Ridge National Laboratory

Palmer Taylor

Zoran Radic

Valery Fokin

K Barry Sharpless

Rakesh Sit

Scott B Hansen

Carlo Ballatore

M G Finn

Lori Jennings

Lukas Gorecki

Jianxin Shi

Aileen Boyd

Davide Comoletti

Gisela-Andrea Camacho-Hernandez

Robyn Flynn

Xiaolin Cheng

Andrey Kovalevsky

In alternative embodiments, provided are uncharged bis-oxime antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). In alternative embodiments, provided are pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound as provided herein.

Centrally active and orally bioavailable uncharged bisoxime antidotes for organophosphate poisoning and methods for making and using them

In alternative embodiments, the invention provides nucleophilic hydroxyimino-acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino-acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.

Centrally active and orally bioavailable antidotes for organophosphate exposure and methods for making and using them

In alternative embodiments, provided are selective agonists having a high affinity for the alpha7 nicotinic acetylcholine receptor (&#x3b1;7 nAChR), assays for selectivity of nicotinic receptor subtype and ligand-gated ion channel subtype based on receptor occupation and response, behavioral assessments for reversing cognitive impairment after scopolamine treatment, enhancing memory retention over time, pharmaceutical compositions and formulations and devices comprising them, and methods for making and using them, including characterizing and efficiently assaying them for receptor subtype selectivity. In alternative embodiments, provided are substituted anti 1,2,3-triazoles compounds with high affinity, and selective binding, for the alpha7 nicotine acetylcholine receptor (&#x3b1;7 nAChR), as exemplified by 5-(1-(2-(Piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1H-indole ('IND1'), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole ('IND8') and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (&#x201c;QND8&#x201d;). In alternative embodiments, provided are products of manufacture such as pumps, devices, syringes and the like comprising a compound, pharmaceutical composition or formulation as provided herein.

Selective alpha-7 nicotinic receptor agonists and methods for making and using them

Provided are N-alkyl imidazole 2-aldoximes, including cationic imidazolium and uncharged tertiary imidazole aldoximes, and compositions and methods for making and using them, including methods for reactivating human butyrylcholinesterase (hBChE) or acetylcholinesterase (hAChE) inhibited by organophosphate (OP). By administration of a composition of the invention, the inactive or conjugated hBChE-OP or hAChE-OP is reactivated and the catalytic cycle of turnover and inactivation of the OP is completed; and in alternative embodiments, secondary mechanisms of reversible protection of hBChE and hAChE from irreversible inactivation by OPs and reactivation of tissue AChE also contribute to overall efficacy.

Catalytic scavengers of organophosphates to potentiate butyrylcholinesterase (hBChE) as a catalytic bioscavenger and methods for making and using them

Disclosed are methods for the preparation and use of labeled AChE and labeled AChE inhibitory conjugate compositions for detecting accumulation of toxic materials such as organophosphates, insecticides, and other nerve agents. Also disclosed are methods for the use of labeled AChE and labeled AChE inhibitory conjugate compositions in a variety of areas, including the detecting of toxic materials in biological samples, in the area of food and water analysis, in environmental monitoring, and in industrial settings.

Ligand sensing fluorescent acetylcholinesterase for detection of organophosphate activity

Provided are methods and compositions for treating autism spectrum disorders by administering an antioxidant or agent that stabilize or enhance expression of altered neuroligins. An aspect of the disclosure includes site-specific delivery of the antioxidant to the endoplasmic reticulum (ER) to reverse incorrect disulfide binding of the protein neuroligin. Also disclosed is a method of targeting the antioxidant to neuroligin by using the calcium binding or other recognition site of neuroligin to bind the antioxidant. The antioxidant can be cysteamine linked to a molecule which binds to a binding site.

Method of promoting delivery of an antioxidant agent to a cell expression neuroligin

Fluorescence based screening assays are provided that allow for the for identification of agents that selectively bind to a ligand-gated ion channel (LGIC) such as a nicotinic acetylcholine receptor (nAChR). Also provided are methods for identifying agents that selectively bind to a neuronal-type nAChR by detecting binding of the agent to anAChBP, which is representative of a neuronal-type nAChR. In addition, compositions and kits for performing such methods are provided.

Methods for identifying agents that modulate LGIC receptor activity

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La Jolla, CA, United States of America

Palmer Taylor