Agonists And Antagonists

Many drugs bind to cholinergic receptors but few of them enter the brain and those that do are not noted for their effects.

AGONISTS

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 ¿6 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.

Pilocarpine, arecoline and, of course, muscarine itself are naturally occurring muscarinic agonists, while oxotremorine is a synthetic one, which, as its name implies, can cause muscle tremor through a central effect.

In view of the preponderance of muscarinic receptors in the CNS and the conceived need to augment the muscarinic actions of ACh in the treatment of Alzheimer's disease, much attention has been given recently to the synthesis of agonists that penetrate the blood-brain barrier, especially those that act specifically on M1 receptors.

Few drugs, apart from nicotine itself, act specifically on nicotine receptors. One is methylcarbachol, which lacks the muscarinic effects of carbachol and another is dimethylphenylpiperazinium (DMPP), which appears to have some selectivity for the neuronal nicotinic receptor. Neither of them can cross the blood-brain barrier.

The Structure Agonist Drugs

Figure 6.6 Structure of some cholinergic agonists and antagonists. Acetylcholine has the structure to activate both muscarinic and nicotinic receptors. Carbachol retains these actions but is longer acting because it lacks the terminal methyl group and is not so readily hydrolysed by cholinesterase (see Fig. 6.1). Methacholine with the methyl side chain lacks nicotinic activity but can be hydrolysed while bethanechol has a similar action but, like carbachol, is not easily hydrolysed. They show chemical similarities to muscarine. Suxamethonium is like two acetylcholine molecules joined together and has transient nicotinic activity at the neuromuscular junction before desensitising (blocking) those receptors. Decamethonium has a similar but much longer blocking action because, unlike suxamethonium, it is not hydrolysed by plasma cholinesterase

Figure 6.6 Structure of some cholinergic agonists and antagonists. Acetylcholine has the structure to activate both muscarinic and nicotinic receptors. Carbachol retains these actions but is longer acting because it lacks the terminal methyl group and is not so readily hydrolysed by cholinesterase (see Fig. 6.1). Methacholine with the methyl side chain lacks nicotinic activity but can be hydrolysed while bethanechol has a similar action but, like carbachol, is not easily hydrolysed. They show chemical similarities to muscarine. Suxamethonium is like two acetylcholine molecules joined together and has transient nicotinic activity at the neuromuscular junction before desensitising (blocking) those receptors. Decamethonium has a similar but much longer blocking action because, unlike suxamethonium, it is not hydrolysed by plasma cholinesterase

Although nicotine receptors are few in number, the proven ability to stimulate NT release may initiate the search for more effective centrally acting agonists.

ANTAGONISTS

The neuromuscular blocking action of the poison J-tubocurarine (curare) has been known for a century. It works by competing with ACh for binding to the nicotinic receptor. Others have been developed such as suxamethonium (succinylcholine) which is essentially two molecules of ACh joined together (Fig. 6.6). Perhaps not surprisingly, it is initially an agonist that causes a depolarisation of muscle fibres and actual twitching, before producing a depolarisation block of transmission. There are a large number of competitive antagonists apart from curare, such as gallamine, pancuronium and atracurium, while decamethonium works like suxamethonium as a depolarising agent. They can be used to produce neuromuscular block and skeletal muscle paralysis in surgery and prevent the damage to limbs that can occur in the electroconvulsive treatment of depression. An interesting pharmacological distinction between these two classes of neuromuscular blocking agents is that the effect of the competitive receptor blockers like curare can be overcome by increasing the concentration of ACh, which is achieved in vivo by giving an anticholinesterase, while the blocking action of the depolarising drugs is not reversed.

Drugs that block the nicotinic receptors on autonomic ganglia, such as hexamethonium, probably do so by actually blocking the Na+ ion channel rather than the receptor. Generally these receptors appear to resemble the central ones more than those at the neuromuscular junction and dihydro-P-erythroidine is one drug that it is an effective antagonist in both ganglia and the CNS.

In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood-brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. This would be the expected effect of a drug that is blocking the excitatory effects of ACh on neurons but since the stimulant action of atropine can be reversed by an anticholinesterase it is still presumed to involve ACh in some way. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15).

DRUGS AND THE DIFFERENT MUSCARINIC RECEPTORS

While five different muscarinic receptors have now been distinguished, atropine and the other antimuscarinics discussed above show little specificity for any of them, although pirenzapine is most active at the M1 receptor. Much effort has been expended in the search for more specific muscarinic agonists and antagonists and while a few compounds have emerged which, from binding studies at least, show some (but never dramatic) selectivity, the results have been somewhat disappointing. As M1 receptors mediate the postsynaptic excitatory effects of ACh while M2 cause autoinhibition of its release, then augmenting ACh activity requires an M1 agonist coupled with an M2 antagonist capable of crossing the blood-brain barrier as well as an M1 antagonist that will not. Even then the peripheral effects of the M2 antagonist such as dry mouth and blurred vision can be unpleasant. Such possible permutations of agonist and antagonists in the treatment of dementia are considered in more detail in Chapter 18.

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    Does methylcarbachol cross blood brain barrier?
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