Channel activators, cholinergic

Brioni JD, O Neill AB, Kim DJ, Buckley MJ, Decker MW, Arneric SP. (1994). Anxiolytic-like effects of the novel cholinergic channel activator ABT-418. J Pharmacol Exp Ther. 271(1) 353-61. 

Buccafusco JJ, Jackson WJ, Terry AV Jr, Marsh KC, Decker MW, Arneric SP. (1995). Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418 a novel cholinergic channel activator for memory enhancement. Psychopharmacology (Berlin). 120(3) 256-66. 

Researchers at Abbott have been investigating the use of pyrrolidinylisoxazolesas nicotinic cholinergic channel activators (138). Until recently, ABT-418 (97) was undergoing clinical trials as a potential treatment for cognitive impairment and decline and for Alzheimer s disease. A short synthesis of ABT-418 was devised starting from commercially avail-... 

ABT-418 [(A)-3-methyl-5-(l-methyl-2-pyrrolidinyl)isoxazole] is a potent cholinergic channel activator and various synthetic routes have been studied for the preparation of large quantities of this compound, required for its evaluation as a safe and effective treatment for Alzheimer s disease <1995TL2563, 1996JOC356, 2004S1859>. 

In a series of substituted 2-arylpyrrolidines in which the substituted aryl group is a bio-isosteric replacement for the pyridine ring of nicotine, it was found that the isoxazole derivative (69) is a potent cholinergic channel activator (116). 

Donnelly-Roherts, D.L., Xue, I.C., Arneric, S.P., Sullivan, J.P., 1996. In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418. Brain Res. 719, 36-44. 

Potter, A., Corwin, J., Lang, J., Lenox, R., Newhouse, P.A., 1999. Aeute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 improved learning in Alzheimer s disease. Psychopharmacology 142, 334-342. 

R. J., Rodrigues, A.D., Sullivan, J.P., 1995. Preclinical pharmacology of ABT-418 A prototypical cholinergic channel activator for the potential treatment of Alzheimer s disease. CNS Drug Rev. 1, 1-26. 

Scheme 29.28 Oxidation of cholinergic channel activator for the treatment of Alzheimer s disease...

Nicotine stimulates central nicotine receptors and also affects other neurotransmission systems, increasing tyrosine hydroxylase activity and elevating noradrenaline (norepinephrine) release from the hippocampus [185], These effects have surprising kinetics since induced modifications persist long after treatment withdrawal. The administration of nicotine to patients raises certain problems, but this line of research has resulted in the development of compounds without the undesirable effects of nicotine itself and are referred to as cholinergic channel activators (for review see [186]). 

Garvey, D. S., Wasicak, J. T., Decker, M. W., Brioni, J. D., Buckley, M. J., Sullivan, J. P, Carrera, G. M., Holladay, M. W., Americ, S. P, Williams, M. Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities. J. Med. Chem. 1994, 57(8), 1055—1059. 

Our data indicate that cholinergic receptors modulate Kv channels. Even though the data do not fully provide the underlying mechanisms of this interaction, they have prompted a modification of our view as to how glomus cells are excited. Neurotransmitters appear to contribute to the excitabdity of glomus cells not only by their immediate and direct action on their receptors, but also by their modulating effects on ion channel activities. 

Nicotine is the main psychoactive ingredient of tobacco and is responsible for the stimulant effects and abuse/ addiction that may result form tobacco use. Cigarette smoking rapidly (in about 3 sec ) delivers pulses of nicotine into the bloodstream. Its initial effects are caused by its activation of nicotinic acetylcholine (nACh) receptors. nACh receptors are ligand-gated ion-channels and pre- and postsynaptically located. Reinforcement depends on an intact mesolimbic dopamine system (VTA). nACh receptors on VTA dopamine neurons are normally activated by cholinergic innervation from the laterodorsal tegmental nucleus or the pedunculopontine nucleus. 

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

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