Acetylation Receptors, nicotinic

As distinct from the acetyl choline receptor of the neuromuscular junction, the acetyl receptors of the viscera are not blocked by nicotine but are blocked by muscarine. Moreover, based on differences in the binding of the muscarinic antagonist, pirenzapine, the muscarinic acetyl choline receptors (mAChRs), are separated into two classes, viz. high affinity mj receptors, and low affinity m2 receptors. The latter predominates in the heart, cerebellum, and smooth muscle broadly. These different receptors mediate quite different actions. 

Acetyl choline is the natural neurotransmitter for the cholinergic receptor. Two distinct receptor subtypes have been characterized based on their binding affinity for either nicotine (189) and (190) or muscarine (191). 

Nicotine is a component of Nicotiana tabacum, the tobacco plant. It is toxic to many insects because of its action upon the nicotinic receptor of acetyl choline. It has served as a model for a new range of insecticides, the neonicotinoids, which also act upon the nicotinic receptor (Salgado 1999). 

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

Figure 13.3. An overview of the chemical events at a cholinergic synapse and agents commonly used to alter cholinergic transmission acetyl CoA, acetyl coenzyme A Ch, choline. Nicotine and scopolamine bind to nicotinic and muscarinic receptors, respectively (nicotine is an agonist while scopolamine is an antagonist). Most anti-Alzheimer drugs inhibit the action of the enzyme cholinesterase.

Assays of acetyl- and butyrylcholine esterases inhibition, as well as of modulation of calcium channels and nicotinic receptors have been conducted in vivo. Moreover, their interaction with the active center of acetylcholine esterase has been simulated by molecular dynamics. For synthesized compounds the IC50 of acetylcholine esterase inhibition was about 9 X M, and for the most active the value was four to five times... 

Muscarinic Receptor Interactions. Excitatory muscarinic effects, such as temporary stimulation of salivation and stimulation of intestinal peristalsis, were seen with 2-PAM. Atropine-like actions were seen at high concentrations (15-20 mg/kg or more), and, when injected rapidly, 2-PAM caused temporary diplopia (nicotinic block) and loss of accommodation in the eye.Both TMB-4 and 2-PAM blocked bradycardia induced by vagal stimulation. At low concentrations, neither compound affected normal intestinal peristalsis, but they did block peristalsis caused by increased vagal stimulation. TMB-4, 2-PAM, and toxogonin antagonized the effect of acetylcholine, acetyl- -methyl-choline, and other agonists on Isolated guinea pig ileum.62... 

The iodinated analogue of A-85380 <1998JME3690>, (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine 241, is a ligand used for single photon emission computerized tomography (SPECT) imaging of human and nonhuman nicotinic acetyl choline receptors in vivo. 

Acetamiprid (Neonicotinoid) (1992) Nippon soda CH, CN 3 / C = N Cl — V-CKl/ N=/ CH3 Nicotinic acetyl-choline receptor agonist... 

Nitenpyram (Nitromethylene neonicotinoid) (1993) Takeda N —a acetyl-choline receptor agonist... 

Figure 9.1. Overview of a cholinergic synapse. The transmitter is synthesized in the presynaphc terminal from choline and acetyl-CoA. Upon release, it binds to the postsynaptic receptor (of either the nicotinic or muscarinic type). Inachvation is by acetylcholinesterase, which is located at the postsynaptic membrane. Choline is taken up again into the presynaphc terminal by sodium and chloride cotransport.

ACh is found to be stored within the terminals of motor neurons. Detailed analysis has demonshated that ACh is stored within small packages called synaptic vesicles that are concenhated around active zones on the presynaptic membrane. These active zones have been identified as specialized sites for neurohansmitter containing vesicle release. The enzyme for synthesizing ACh from choline and acetyl-Co A, choline acetyl transferase, is also found within the presynaptic terminal. Choline acetyl transferase is found in the cytoplasm. When ACh is synthesized it is pumped into synaptic vesicles by means of a specific carrier molecule located in the vesicle membrane. Once released, ACh subsequently diffuses across the synapse and activates nicotinic ACh receptors localized on the plasma membrane of the postsynapdc muscle cell producing depolarization of the muscle (see below). 

Eldefrawi and Eldefrawi [98] reported the purification of the acetylcholine of Torpedo electroplax on an affinity column consisting of cobra (Naja naja siamensis) toxin coupled to Sepharose 4B. Desorption with 10 mM benzoquinonium produced a protein that bound [ I]a-bungarotoxin but not [ H]acetyl-choline. However, desorption with 1 mM carbamylcholine gave a receptor protein that bound pH]acetylcholine decamethonium, [ H]nicotine [ C]dimethyl-(-l-)-tubocuranrine, and [ I]a bungarotoxin. Schmidt and Raftery [99] also purified acetylcholine receptor, from Narcine, on a N-(e-aminohexanoyl)-3-aminopropyltrimethyl-ammonium bromide-HBr-agarose column. 

Patrick, J. Heinemarm, S. Members of a nicotinic acetyl-chohne receptor gene family are expressed in different regions of the mammalian central nervous system. Cell 47. 1987, 48, 965-973. 

Glennon, R.A., Dukat, M., 1999b. Nicotine analogs structure-affinity relationships for central acetyl-cholinergic receptor binding. In Yamamoto, I., Casida, J.E. (Eds.), Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Spinger-Verlag, Tokyo, 237-252. 

For this purpose we have determined whether an alkaloid can displace a specifically bound ligand from a neuroreceptor, such as ot, 0t2 adrenergic receptors, serotonin receptor [5-HT2], and nicotinic and muscarinic acetyl choline receptors (Table 15) obtained from porcine brains [69-72]. In addition, we have determined whether the same alkaloids inhibit acetylcholine esterase, whether they intercalate DNA, inhibit DNA polymerase I, reverse transcriptase, protein biosynthesis and membrane stability [40, 73]. The results can be summarized as follows ... 

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