A4 32 Nicotinic acetylcholine receptor

Zhang, X., Gong, Z.-H., Hellstrom-Lindahl, E., Nordberg, A. Regulation of a4(32 nicotinic acetylcholine receptors in M10 cells following treatment with nicotinic agents. Neuroreport. 6 313, 1994. 

Buisson, B., Bertrand, D. Chronic exposure to nicotine upregulates the human a4(32 nicotinic acetylcholine receptor function. J. Neurosci. 21 1819, 2001. 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Kulak JM, Nguyen TA, Olivera BM, McIntosh JM (1997) Alpha-conotoxin Mil blocks nicotine-stimulated dopamine release in rat striatal synaptosomes. J Neurosci 17 5263-5270 Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J (1997) Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca + permeabihty, conductance, and gating of human a4 32 nicotinic acetylcholine receptors, J Neurosci 17 9035-9047 Kuryatov A, Olale FA, Choi C, Lindstrom J (2000) Acetylchohne receptor extracellular domain determines sensitivity to nicotine-induced inactivation, Eur J Pharmacol 393 11-21 Langley JN (1880) On the antagonism of poisons. J Physiol 3 11-21... 

Rodriguez-Pinguet NO, Pinguet TJ, Figl A, Lester HA, Cohen BN (2005) Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca + activation of the a4 32 nicotinic acetylcholine receptor. Mol Pharmacol 68 487-501 Romano C, Goldstein A (1980) Stereospecific nicotine receptors on rat brain membranes. Science 210 647-650... 

The synthesis of a new precursor of 5-IA-85380, a specific radiotracer for a4(32 nicotinic acetylcholine receptors, that is, (A)-5-trimethylstannyl-3-(2-azetidinylmethoxy)pyridine 109, has been accomplished in six steps and 62% overall yield by functional group transformations of the carboxyl group in (A)-azetidine-2-carboxylic acid 23 (Scheme 22) <2004TL3607>. 

Figure 5. Inward currents induced by bath-applied acetylcholine (ACh) and imidacloprid of the wild-type (A) a4(32 nicotinic acetylcholine receptor and the T77R E79V double mutant (B) expressed in Xenopus laevis oocytes. Reproduced from reference [21] with permission of American Society for Pharmacology and Experimental Therapeutics.

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... 

Rush R, Kuryatov A, Nelson ME, Lindstrom J (2002) First and second transmembrane segments of a3, a4, 32 and 34 nicotinic acetylcholine receptor subunits influence the efiBcacy and potency of nicotine. Mol Pharmacol 61 1416-1422... 

Buisson B. and Bertrand D. (1998). Open-channel blockers at the human a4/32 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53 555-563. 

Pereira, E.F.R. et al., Physostigmine and galanthamine probes for a novel binding site on the a4 32 subtype of neuronal nicotinic acetylcholine receptors stably expressed in fibroblast cells, J. Pharmacol. Exp. Ther., 270, 768, 1994. 

Acetylcholine Binding Protein, Chicken a4 Subunit, Chicken (32 Subunit, Drosophila mdanogasterDal Subunit, Homology Modeling, Loop D, Neonicotinoid, Nicotinic Acetylcholine Receptor, Two-Electrode Voltage-Clamp... 

Figure 2.14 Pyridine bioisosteric replacement leadingto selective inhibitors of (a4)2( 32)3 nicotinic acetylcholine receptor.

Similar nAChRs are also found in the brain.621 631 632 However, they are not identical but have at least 17 differing amino acid sequences (al-alO, (31-(34, y, 8, and e). The neuromuscular junction receptor (muscle type) from fish is described as (al)2 (31 my / S.626 The brain contains homopentamers of subunits a7, a8, and a9 as well as various heteropentamers. The various forms possess different affinities for acetylcholine and for antagonists such as nicotine.633 634 In the brain the highest affinity for nicotine is shown by an a4 32 form, which represents over 80% of the nAChR in mammalian brain.634 635 Knockout mice in which the (32 subunit gene has been deleted lose their sensitivity to nicotine. 

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