Neuronal nicotinic acetylcholine receptor modulators

DISCOVERY OF ABT-594 AND RELATED NEURONAL NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AS ANALGESIC AGENTS ... 

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Bannon, A. W., Decker, M. W., Holladay, M. W., Curzon, P., Donnelly-Roberts, D. L., Puttfarcken, P. S., Bitner, R. S., Diaz, A., Dickenson, A. H., Porsolt, R. D., Williams, M., Arneric, S. P. Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors, Science 1998, 279, 77-81. 

Hurst RS, Hajos M, Raggenbass M, Wall TM, Higdon NR, et al. 2005. A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor In vitro and in vivo characterization. J Neurosci 25 4396-4405. 

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Holladay, M.W., Cosford, N.D.P., McDonald, I.A., 1999. Natural products as a source of nicotinic acetylcholine receptor modulators and leads for dmg discovery. In Americ, S.P., Brioni, J.D. (Eds.), Neuronal Nicotinic Receptors Pharmacology and Therapeutic Opportunities. Wiley-Liss, New York, pp. 253-270. 

Chapter 2 is an intriguing account of the development of a potent analgesic compound that works via modulation of neuronal nicotinic acetylcholine receptors. The clinical candidate ABT-594 can be traced to the unlikely origin of the natural product epibatidine from the skin of an Ecuadoran frog and a muscarinic receptor program geared towards treating Alzheimer s disease. 

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Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR). Activation of this receptor depolarizes target cells (see Ch. 11). nAChRs are composed of five subunits surrounding a central ion-channel pore. Twelve different nicotinic receptor subunits are expressed in the nervous system (a2-oclO and (32—134). Of these, a subset is expressed in the VTA (a3-a7 and P2—134). It is thought that a7 receptors form homomeric receptors a3, a4 and a6 form heteromeric channels with 02 or 04 and a5 and 03 can associate with other a/0 pairs. Studies in knockout mice implicate several subunits in the ability of nicotine to modulate dopamine neurons (a4, a6, a7, 02, 03) but... 

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Gentry CL, Lukas RJ (2002) Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure. Curr Drug Targets CNS Neurol Disord 1 359-385 Gerzanich V, Wang F, Kuryatov A, Lindstrom J (1998) Alpha 5 subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal alpha 3 nicotinic receptors. J Pharmacol Exp Ther 286 311-320... 

Alkondon M, Rocha ES, Maelicke A, Albuquerque EX (1996) Diversity of nicotinic acetylcholine receptors in rat brain. V. alpha-Bungarotoxin-sensitive nicotinic receptors in olfactory bulb neurons and presynaptic modulation of glutamate release. J Pharmacol Exp Ther 278 1460-71... 

Scholz KP, Miller RJ (1992) Inhibition of quantal transmitter release in the absence of calcium influx by a G protein-linked adenosine receptor at hippocampal synapses. Neuron 8 1139-50 Seddik R, Schlichter R, Trouslard J (2006) Modulation of GABAergic synaptic transmission by terminal nicotinic acetylcholine receptors in the central autonomic nucleus of the neonatal rat spinal cord. Neuropharmacology 51 77... 

Recent data indicate that AEA can interact with known GPCRs for other neuronal mediators or with novel GPCRs. AEA was found to exhibit inhibitory activity on 5-hydroxy-tryptamine receptors (Kimura et al., 1998), and both muscarinic and nicotinic acetylcholine receptors (Lagalwar et al., 1999 Oz et al., 2003). Except for the inhibitory effect on nACh alpha7 nicotinic receptors (IC50 = 218 wM), however, AEA appears to modulate the binding and functional activity of 5-HT and acetylcholine only at concentrations (> 5 iM) that are not likely to occur in vivo. Regarding... 

Galanthamine is the only alkaloid of this class that has already found apphcation in medicine. It is approved for the symptomatic treatment of Alzheimer s disease in Europe and the United States. Its mode of action consists in a competitive and reversible inhibition of acetylcholinesterase, which leads to an increased concentration of acetylcholine at neuronal synapses. In addition, galanthamine acts as an allosteric modulator on nicotinic acetylcholine receptors. Since a characteristic featnre of Alzheimer s disease is the loss of acetylcholinergic neurons concomitant with decreased levels of acetylcholine, galanthamine can, at least partially, compensate the damage and thus enhance cognitive functions in Alzheimer s patients. 

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