Acetylcholine structure-activity relationships

The necessity to design compounds that would serve as therapeutic alternatives to acetylcholine and as probes to study the role of acetylcholine in neurotransmission led to an exhaustive study of the structural features required for the action of acetylcholine. Structure-activity relationships that developed from these studies have provided the basis for the design of all muscarinic agonists currently used as therapeutic agents. 

Albuquerque EX, Aracava Y, Cintra WM, Brossi A, Schonenberger B, Deshpande SS. Structure-activity relationship of reversible cholinesterase inhibitors activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex. Braz. J. Med. Biol. Res. 21 1173-1196, 1988. 

The cholinesterases, acetylcholinesterase and butyrylcholinesterase, are serine hydrolase enzymes. The biological role of acetylcholinesterase (AChE, EC 3.1.1.7) is to hydrolyze the neurotransmitter acetylcholine (ACh) to acetate and choline (Scheme 6.1). This plays a role in impulse termination of transmissions at cholinergic synapses within the nervous system (Fig. 6.7) [12,13]. Butyrylcholinesterase (BChE, EC 3.1.1.8), on the other hand, has yet not been ascribed a function. It tolerates a large variety of esters and is more active with butyryl and propio-nyl choline than with acetyl choline [14]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in their specificity with respect to the acyl moiety of the substrate [15]. AChE hydrolyzes ACh at a very high rate. The maximal rate for hydrolysis of ACh and its thio analog acetyl-thiocholine are around 10 M s , approaching the diffusion-controlled limit [16]. 

In contrast to acetylcholinesterase, which is selective for acetylcholine, butyryl-cholinesterase tolerates a wider variety of esters and is more active with butyryl-and propionylcholines than acetylcholine [7]. Structure-activity relationship studies have shown that different steric restrictions in the acyl pockets of AChE and BChE cause the difference in specificity to the acyl moiety of the substrate [6]. 

Nicolotti, O., Pellegrini-Calace, M., Altomare, C., Carotti, A., Carrieri, A., and Sanz, F. 2002. Ligands of neuronal nicotinic acetylcholine receptor (nAChR) Inferences from the Hansch and 3-D quantitative structure-activity relationship... 

Holladay, M. W., Lebold, S. A., Lin, N. H. Structure-activity relationships of nicotinic acetylcholine receptor agonists as potential treatments for dementia. Drug. Dev. Res. 1995(35), 191-213. 

Caldwell, W.S., Benchenif, M., Bhatti, B.S., Deo, N.M., Dobson, G.P., Dull, G.M., Lipiello, P.M., Lovette, M.E., Miller, C.H., Ravard, A., Schmitt, J.D., Crooks, P.A., 1997. Synthesis and structure-activity relationships of analogs of RJR-2403, a CNS-selective nicotinic agonist. Abstracts of International Business Communications Symposium on Nicotinic Acetylcholine Receptors as Pharmaceutical Targets, Washington, DC, July 24-25. 

D. J., Campbell, J.E., Kuntzweiler, T.A., Donnelly-Roberts, D.L., Piattoni-Kaplan, M Briggs, C.A., Williams, M., Arneric, S.P., 1998. Identification and structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors. J. Med. Chem. 41, 407-412. 

Most of what we know of the structure of the muscarinic receptor has been gleaned from studies of structure-activity relationships among agonists that mimic acetylcholine at the postganglionic synapses. These are the receptors traditionally termed muscarinic, but it must be kept in mind that this is a name of historical origin. Muscarine has no use in human medicine. Not much attention can be given to information derived from antagonists because these... 

T0nder JE, Olesen PH (2001) Agonists at the a4P2 nicotinic acetylcholine receptors structure-activity relationships and molecular modelling. Curr Med Chem 8 651-674... 

The mechanism of neurotoxin action on the nerve systems involves blocking of the nerve impulse transmission at the site of the neuromuscular junction by strong specific binding to the acetylcholine receptor in the postsynaptic membrane, thus interrupting the pathway whereby the neurotransmitter released in the synaptic cleft could affect the excitability of the postsynaptic neuron. The availability of highly purified acethylcholine receptor protein(24) allows a direct study of the structure-activity relationship of neurotoxins and their bindings with the receptor. 

Structure activity relationship In terms of spasmolytic activity of Kavaln (15) and other active constituents of P. methystiowrfi was reported. They all Inhibited or abolished contractions of Isolated guinea pig Ileum induced by acetylcholine, histamine, 5-HT or nicotine and were halt as active as papavarlne sulfate. Reduction of the styryl double bond In Kavaln reduced whereas unsaturation In the pyrone ring and eubstltution by methylenedloxy>... 

Matsuo H, Tomizawa M, Yamamoto 1 (1998) Structure-activity relationships of acychc nicotinoids and neonicotinoids for insect nicotinic acetylcholine receptor/ion channel complex. Arch Insect Biochem Physiol 37 17-23... 

R 442 F. Mesnard and R.G. Ratcliffe, NMR Analysis of Plant Nitrogen Metabolism , Photosynth.Res., 2005,83,163 R 443 E.L. Millard, N.L. Daly and DJ. Craik, Structure-Activity Relationships of a-Conotoxins Targeting Neuronal Nicotinic Acetylcholine Receptors , Eur.J.Biochem., 2004,271,2320 R 444 K. Moebius, A. Savitsky, A. Schnegg, M. Plato and M. Fuchs, High-Field EPR Spectroscopy Applied to Biological Systems Characterization of Molecular Switches for Electron and Ion Transfer , Phys.Chem.Chem.Phys., 2005,7,19... 

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