Medical brain Notes 3

  Pharmacology of cholinergic synapses As we have seen [in a previous chapter], acetylcholine oc-curs in synapses in both the somatic and the autonomic ner-vous system. The nicotinic acetylcholine receptor is found in the motor endplate of the skeletal muscle, and in both the sympathetic and the parasympathetic ganglia of the periph-eral autonomic system. Muscarinic acetylcholine receptors are found at the endings of all secondary neurons within the parasympathetic part of the peripheral autonomous system. In addition, acetylcholine receptors of both types also oc-cur in the brain. Drugs with a useful degree of selectivity for each of these targets are available and used in practical medicine. Selectivity is based on two principles:   1.    Receptor type and subtype specificity of agonists or antagonists, and   2.    Exclusion by the blood brain barrier of drugs intended for peripheral action.   One particular feature of cholinergic synapses is th...

  Structure and function of the nicotinic acetylcholine receptor The nicotinic acetylcholine receptor (NAR) is the most widely studied receptor ion channel. This is due to a very practical reason – availability. The receptor can be isolated in high yield from electric eel or electric ray, both of which use strong electric discharges to incapacitate their prey or for defence. In the electric organs of these fish, the receptor occurs in abundance in stacks of excitable cells (Figure 9.2). Importantly, however, the NAR and voltage-gated ion channels only occur on one side of the cell.   In the resting state, both sides of the cell will have the same membrane potential. As a consequence, the electric field vectors within the cell and within the entire stack will can-cel each other out (Figure 9.2a). Electric stimulation will depolarize one membrane in each cell and invert its electri-cal field. Now, all of a sudden, all field vectors in the entire stack will point into the same di...

  Cholinergic agonists Drugs that stimulate acetylcholine receptors are conven-tionally called `direct agonists', as opposed to `indirect ag-onists', which are inhibitors of acetylcholinesterase (see below). Direct cholinergic agonists are used in a variety of clinical applications. Acetylcholine itself is not a very use ful drug because it gets so rapidly hydrolysed. Just like in the experiment above (Figure 9.7), its action  in vivo  sub-sides as a matter of seconds after discontinuation. Most cholinergic agonists that are in clinical use are partially or completely resistant to degradation by cholinesterase and thus will remain active for extended periods of time.   1. Muscarinic agonists Two such agonists are shown in Figure 9.9. In the struc-ture of carbamoylcholine, the acetyl group is replaced by a carbamoyl group. This agonist is only very slowly de-graded by cholinesterase. It resembles acetylcholine in being active at both muscarinic and nicotinic synapses....

  Cholinergic antagonists Cholinergic antagonists have a larger therapeutic role than agonists. Again, we can distinguish drugs that selectively affect nicotinic and muscarinic receptors.   1. Muscarinic antagonists   The classical muscarinic antagonists are atropine and the closely similar scopolamine. Atropine (Figure 9.12) will to some extent enter the brain and cause upheaval there as well – this is reflected in the German name of the plant contain-ing it ( Tollkirsche  = "crazy-cherry"). It is used for local ap-plication to the eye (widening the pupil, relaxing the ciliary muscle in diagnostic procedures), and during surgery to re-lax the airways and suppress salivation, both of which will help to avoid respiratory problems during narcosis. Iprat-ropium is used for oral and inhalation treatment to relax the airways in asthma, and occasionally to speed up a slow atri-oventricular node in the heart (cf. the preceding chapter). It is preferred over atropin in most ...

  Cholinesterase antagonists The last group of agents that affect cholinergic synaptic transmission are blockers of cholinesterase. This enzyme has a catalytic mechanism that is analogous to that of chy-motrypsin and related proteases. In chymotrypsin, there is a `catalytic triad', consisting of a serine, a histidine, and an aspartic acid side chain in the active site. The only dif-ference with cholinesterase is that a glutamate residue re-places the aspartate – and this difference is insignificant, because glutamate and aspartate share a carboxyl group, which is the essential feature for catalysis.   Within this catalytic triad, the glutamate and the histidine residues cooperate to effect deprotonation of the hydroxyl group in the serine side chain (Figure 9.15). The anionic oxygen is a powerful nucleophile that will readily attack the carbonyl carbon of the ester bond in acetylcholine. This will release choline and leave the acetyl group attached (via another ester bond) to ...