Acetylcholine bound

Given the difficulty of obtaining three-dimensional crystals of membrane proteins, it is not surprising that the electron microscope technique is now widely used to study large membrane-bound complexes such as the acetylcholine receptor, rhodopsin, ion pumps, gap junctions, water channels and light-harvesting complexes, which crystallize in two dimensions. 

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 concept of property space is progressively being used to gain a deeper understanding of the dynamic behavior of a single compound in different media (as we illustrate below with acetylcholine, see Section 1.4.2) or bound to biological targets (the carnosine-carnosinase complex, see Section 1.4.3), but it can be used also with a set of compounds to derive fertile descriptors for dynamic QSAR analyses (4D QSAR, see Section 1.4.4). 

Dunn SMJ, Blanchard SG, Raftery MA. 1980. Kinetics of carbamoylcholine binding to membrane-bound acetylcholine receptor monitored by fluorescence changes of a covalently bound probe. Biochemistry 19 5645-5652. 

Griinhagen HH, Iwatsubo M, Changeux JP. 1977. Fast kinetic studies on the interaction of cholinergic agonists with the membrane-bound acetylcholine receptor from Torpedo marmorata as revealed by quinacrine fluorescence. Fur J Biochem 80 225-242. 

Representative data for [ H]acetylcholine binding to the membrane-bound Torpedo nAChR. Bindng was measured either by equilibrium dialysis (closed circles) as described in Protocol 4.1 or by centrifugation (open squares, see Protocol 4.2). Estimated Kd values from nonlinear regression curve fitting were 12 nM and 10 nM, respectively with corresponding Rq values of 0.14 ulM and 0.135 ulM... 

Most of the experimental evidence came initially from studies of the frog motor end-plate, where it was shown that the desensitization of the nicotinic receptor caused by continuous short pulses of acetylcholine was associated with a slow-conformational change in that the ion channel remained closed despite the fact that the transmitter was bound to the receptor surface. 

Lack of selectivity (C). Despite appropriate dosing and normal sensitivity, undesired effects can occur because the drug does not specifically act on the targeted (diseased) tissue or organ. For instance, the antichoUnergic, atropine, is bound only to acetylcholine receptors of the muscarinic type however, these are present in many different organs. 

Measurement of the rates of dissociation of enzyme-substrate and protein-ligand complexes, usually promoted by dilution. The utility of dissociation kinetics is well illustrated in the report of Dunn and Raftery who examined the kinetics of pH]acetylcholine and [ H]sub-eryldicholine dissociation from the membrane-bound... 

Ulrich H, IppoKto JE, Pagan ORet al (1998) In vitro selection of RNA molecules that displace cocaine from the membrane-bound nicotinic acetylcholine receptor. Proc Nad Acad Sci USA 95 14051-14056... 

Mechanism of Action A cholinergic agent that prevents destruction of acetylcholine byinhibitingthe enzyme acetylcholinesterase, thus enhancing impulse transmission across the myoneural junction. Therapeutic Effect Produces miosis increases intestinal, skeletal muscle tone stimulates salivary and sweat gland secretions. Pharmacokinetics Not protein bound. Excreted unchanged in urine. Half-life Unknown. 

Certain proteins, peptides, steroids, and other small organic molecules, serve as cell messengers or mediators of signals. Hydrophilic mediators activate receptors at the surface of the target cell. Acetylcholine is a common example of such signaling molecules. It becomes bound on the exterior surface at the acetylcholine receptor of the nervous system, opening the channel. 

---