Acetylcholine transporter

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

The vesicular acetylcholine transport can be inhibited by vesamicol and several related compounds. Vesami-col competitively inhibits transport by binding to a cytoplasmic domain on VAChT with a Kd of 5 nM. Vesamicol binding can be used to estimate transporter number, but neither vesamicol nor its analogues are currently used clinically. 

Capece, M. L., Efange, S. M. Lydic, R. (1997). Vesicular acetylcholine transport inhibitor suppresses REM sleep. Neuroreport 8, 481-4. 

Parsons, S. M., Bahr, B. A., Rogers, G. A. et al. (1993a). Acetylcholine transporter-vesamicol receptor pharmacology and structure. Prog. Brain Res. 98, 175-81. 

Varoqui, H., Mennier, F.-M., Mennier, F. A. etal. Expression of the vesicular acetylcholine transporter in mammalian cells. Prog. Brain Res. 109 83-95,1996. 

It is now possible to image not only postsynaptic, but pre-synaptic and intrasynaptic neurotransmission (Fig. 58-5). Presynaptic sites, such as the dopamine transporter and the serotonin transporter the presynaptic dopamine vesicular transporter (VMAT-2) and the acetylcholine transporter extrasynaptic sites such as the enzymes which break down neurotransmitters, e.g. MAO A and MAO B with radioligands that bind to post or pre-synaptic sites, i.e. dopamine competing with radioligands such as UC raclopride (see Fig. 58-9) (PET (Fig. 58-10) can be measured under basal conditions or following drugs which either decrease (e.g. AMPT) or increase (e.g. intravenous amphetamine) intrasynaptic dopamine. 

During the synthesis of ligands for the vesicular acetylcholine transporter, a octahy-droquinoline nucleus 361 was prepared via a ring-expansion rearrangement followed by a hydride reduction (equation 140). The yield was moderate but only one lactam 360 was produced by the Beckmann rearrangement. 

Parsons SM, Prior C, Marshall IG. Acetylcholine transporter, storage, and release, Int Rev Neurobiol 1993 35 279-390. 

Prado, V. F., Martins-Silva, C., de Castro, B. M., lima, R. F., Barros, D. M., Amaral, E., et al. (2006) Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron 51, 601-612. 

Alfonso A, Grundahl K, Duerr JS, Han HP, Rand JB (1993) The Caenorhabditis elegans unc-17 gene a putative vesicular acetylcholine transporter. Science 261 617-19. 

Anderson DC, King SC, Parsons SM (1983) Pharmacological characterization of the acetylcholine transport system in purified Torpedo electric organ synaptic vesicles. Mol Pharmacol 24 48-54. 

Bahr BA, Clarkson ED, Rogers GA, Noremberg K, Parsons SM (1992) A kinetic and allosteric model for the acetylcholine transporter-vesamicol receptor in synaptic vesicles. Biochemistry 31 5752-5762. 

Bravo DT, Kolmakova NG, Parsons SM (2005) New transport assay demonstrates vesicular acetylcholine transporter has many alternative substrates. Neurochem Int 47 243-247. 

Erickson JD, Varoqui H, Schafer MK, Modi W, Diebler MF, Weihe E, Rand J, Eiden LE, Bonner TI, Usdin TB (1994) Functional identification of a vesicular acetylcholine transporter and its expression from a cholinergic gene locus. J Biol Chem 269 21929-21932. 

Schafer MK, Weihe E, Varoqui H, Eiden LE, Erickson JD (1994) Distribution of the vesicular acetylcholine transporter (VAChT) in the central and peripheral nervous systems of the rat. J Mol Neurosci 5 1-26. 

Scheunemann M, Sorger D, Wenzel B, Heinitz K, Schliebs R, Klingner M, Sabri O, Steinbach J (2004) Synthesis of novel 4- and 5-substituted benzyl ether derivatives of vesamicol and in vitro evaluation of their binding properties to the vesicular acetylcholine transporter site. Bioorg Med Chem 12 1459-1465. 

Song H, Ming G, Fon E, Bellocchio E, Edwards RH, Poo M (1997) Expression of a putative vesicular acetylcholine transporter facilitates quantal transmitter packaging. Neuron 18 815-826. 

Tayebati SK, Di Tullio MA, Amenta F (2004) Effect of treatment with the cholinesterase inhibitor rivastigmine on vesicular acetylcholine transporter and choline acetyltransferase in rat brain. Clin Exp Hypertens 26 363-373. 

Varoqui H, Erickson JD (1996) Active transport of acetylcholine by the human vesicular acetylcholine transporter. J Biol Chem 271 27229-27232. 

Acethylcholine synthesis and release In the presynaptic cholinergic terminal. Ach, acetylcholine ChAT, choline acetyltransferase VAChT, vesicular acetylcholine transporter AChE, acetylcholineesterase CHT, choline transporter... 

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