Nicotinic acetylcholine receptors, neuronal agonists

Coe, J.W. Brooks, P.R. Wirtz, M.C., et al. 3,5-Bicyclic aryl piperidines a novel class of a4P2 neuronal nicotinic acetylcholine receptor partial agonists for smoking cessation. Bioorg. Med. Chem. Lett. 2005, 15, 4889 897. 

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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Yates SL, Bencherif M, Fluhler EN, LippieUo PM (1995) Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to mainstream cigarette smoke or alpha 4 beta 2 receptors to nicotine, Biochem Pharmacol 50 2001-2008 Yeomans J, Baptista M (1997) Both nicotinic and muscarinic receptors in ventral tegmental area contribute to brain-stimulation, Pharmacol Biochem Behav 57 915-921 Yoshida M, Yokoo H, Tanaka T, Mizoguchi K, Emoto H, Ishii H, Tanaka M (1993) Facilitatory modulation of mesolimbic dopamine neuronal-activity by a mu-opioid agonist and nicotine as examined with in-vivo microdialysis. Brain Res 624 277-280... 

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Schneider JS, Pope-Coleman A, Van Velson M, Menzaghi F, Lloyd GK (1998) Effects of SIB-1508Y, a novel neuronal nicotinic acetylcholine receptor agonist, on motor behavior in parkinsonian monkeys. Mov Disord 73 637-642. 

Thomas, P, Stephens, M., Wilkie, G., Amar, M., Lunt, G. G., Whiting, P, Gallagher, T, Pereira, E., Alkondon, M., and Albuquerque, E.X. 1993. (+)-Anatoxin-a is a potent agonist at neuronal nicotinic acetylcholine receptors. JNeurochem 60, 2308-2311. 

Decker MW, Meyer MD. Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics. 59. Biochem. Pharmacol. 1999 58 917-923. 

Nicotine is an agonist to the neuronal nicotinic acetylcholine receptors (nAChR). These receptors are the likely site at which nicotine exerts its central actions. Evidence supports the involvement of the central nAChR in neurotransmitter release (195), and a large body of evidence indicates that dopamine release from dopaminergic neurons is mediated by activation of the brain nAChRs (196). It has also been shown that both nicotinic receptors and muscarinic receptors in the ventral tegmental area (VTA) activate the dopaminergic neurons and thus play a role in the reward effect of nicotine (197). In addition, animal data sug-... 

Pereira, E.F.R. et ah. Identification and functional characterization of a new agonist site on nicotinic acetylcholine receptors of cultured hippocampal neurons, J. Pharmacol. Exp. Ther., 265, 1474, 1993. 

Schrattenholz, A. et al.. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol. Pharmacol., 49, 1, 1996. 

Zheng, F Bayram, E Sumithran, S.P., Ayers, J.T., Zhan, C.-G., Schmitt, J.D., Dwoskin, L.P. and Crooks, P.A. (2006) QSAR modeling of mono-and bis-quaternary ammonium salts that act as agonists at neuronal nicotinic acetylcholine receptors mediating dopamine release. Bioorg. Med. Chem., 14, 3017-3037. 

Lloyd, G.K.. Menzaghi, F Bontempi, B., Suto. C.. Siegel, R., Akong, M. et al., 1998. The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents. Life Sci. 62, 1601-1606. 

Hibbs RE, Sulzenbacher G, Shi J, Talley TT, Conrod S, Kem WR, Taylor P, Marchot P, Bourne Y (2009) Stmctural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal a7 nicotinic acetylcholine receptor. EMBO J 28 3040-3051... 

Jensen AA, Mikkelsen I, Frolund B, et al. Carbamoylcholme homologs novel and potent agonists at neuronal nicotinic acetylcholine receptors. Mol Pharmacol. 2003 64 865-875. 

Cholinergic receptors Receptors for acetylcholine are classified into muscarinic (muscarine is a selective agonist) and nicotinic (nicotine is a selective agonist). There are five muscarinic (mj to m5) and two nicotinic (neuronal, or ganglionic, and skeletal muscular) subtypes. 

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