Muscarinic antagonist

The first antagonists were natural products and in particular alkaloids (nitrogen-containing compounds derived from plants). 

Atropine (Fig. 11.25) has a chiral centre ( ) and therefore two enantiomers are possible. Usually, natural products exist exclusively as one enantiomer. 

This is also true for atropine which is present in the plant species Solanaceae as a single enantiomer called hyos-cyamine. However, as soon as the natural product is extracted into solution, the chiral centre racemizes such that atropine is obtained as a racemic mixture and not as a single enantiomer The chiral centre in atropine is easily racemized since it is next to a carbonyl group. The proton attached to the chiral centre is acidic and as a result is easily replaced. 

Atropine was obtained from the roots of belladonna (deadly nightshade) in 1831. It was once used by Italian women to dilate the pupils of the eye in order to appear more beautiful (hence the name belladonna). 

Hyoscine (or scopolamine) (Fig. 11.26) is also obtained from solanaceous plants and is very similar in structure to atropine. It has been used as a truth drug. 

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FIGURE 4.14 Effects of G-protein on the displacement of the muscarinic antagonist radioligand [sH]-L-quinuclidinyl benzylate by the agonist oxotremorine. Displacement in reconstituted phospholipid vesicles (devoid of G-protein sububits) shown in filled circles. Addition of G-protein (Go 5.9 nmol Py-subunit/3.4 nmol ao-IDP subunit) shifts the displacement curve to the left (higher affinity, see open circles) by a factor of 600. Data redrawn from [14]. 

The ACh-binding pocket partially overlaps with that of competitive muscarinic antagonists such as atropine, scopolamine, or quinuclidinylbenzilate. However, antagonists usually form additional strong interactions with hydrophobic receptor residues, thus stabilizing the inactive state of the receptor [1,3]. 

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. 

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). 

Jacobson, K.A. et al. (1995) Molecular probes for muscarinic receptors Functionalized congeners of selective muscarinic antagonists. Life Sci. 56(11/12), 823-830. 

Henis, Y. I. and Sokolovsky, M. (1983) Muscarinic antagonists induce different receptor conformations in rat adenohypophysis. Mol. Pharmacol. 24, 357-365. 

Chiba, T., Bharucha, A.E., Thomforde, G.M., Kost, L.J., and Phillips, S.F., Model of rapid gastrointestinal transit in dogs effects of muscarinic antagonists and a nitric oxide synthase inhibitor, Neurogastroenterol. Motil., 14, 535, 2002. 

There is also evidence for cholinergic involvement in caffeine analgesia (Ghelardini et al. 1997). The muscarinic antagonists atropine and pirenzepine, and the choline uptake inhibitor hemicholinium-3 prevent caffeine analgesia. In contrast, it was unaffected by an opioid antagonist (naloxone) or a tyrosine hydroxylase inhibitor (o-methyl-p-tyrosine). 

Grasby PM, Frith CD, Paulesu E, Friston KJ, Frackowiak RS, Dolan RJ. (1995). The effect of the muscarinic antagonist scopolamine on regional cerebral blood flow during the performance of a memory task. Exp Brain Res. 104(2) 337-48. 

Ziskind AA. (1988). Transdermal scopolamine-induced psychosis. Postgrad Med. 84(3) 73-76. Zoltoski RK, Velazquez-Moctezuma J, Shiromani PJ, Gillin JC. (1993). The relative effects of selective Ml muscarinic antagonists on rapid eye movement sleep. Brain Res. 608(2) 186-90. 

Cognitive enhancing effects of 5-HT3 receptor antagonists have been observed in several animal models, using both normal animals and animals in which a cognitive deficit has been induced by the administration of the muscarinic antagonist scopolamine [41]. An example is the Wisconsin test, in which marmosets learn to discriminate which of two objects conceal a food reward and, after learning this, the task is reversed such that the food is hidden beneath the other object. Treatment with ondansetron has been shown to enhance the ability of marmosets to learn the reversal task. 

To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed Mi receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the Mi and M2 receptors occur in the brain. Recent studies have shown that Mi and M3 are located posts)maptically in the brain whereas the M2 and M4 receptors occur pres)maptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the Mi, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8). 

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