Acetyl choline analog

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]. 

The principle of conformational restriction was first applied to characterize the bioactive conformation of acetyl choline acting at the muscarinic and nicotinic receptors. Conformational restriction has been applied to many other small ligands (e.g. see reviews by Martin-Smith et al., Portogh-ese, Mutschler and Lambrecht, and Casy et but the work on acetylcholine analogs exemplifies the necessary ideas and techniques required to understand the general approach, as well as its strengths and limitations, when applied to small molecules. 

The crystal structures of certain nicotinic agents, for example, acetyl a-methylcholine (32)and lactoylcholine (17in Table 2.1), have torsion angle (rg and T3) features similar to most muscarinic agents (262). In eontrast, some cyclic analogs of aryl choline ethers exhibit maximum nicotinic effects when the Tg is antiplanar ("transoid") (98). 

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