61
5
Acetylcholine is degraded by acetylcholine esterase. Inhibitors of acetylcholine esterase
thus prolong and increase the synaptic transmission by acetylcholine. Physostigmine, an
indole alkaloid of the Calabar bean (Physostigma venenosum), is a reversible acetylcholine
esterase inhibitor. It mainly targets the acetylcholine in postganglionic parasympathetic
neurons and thus indirectly acts like muscarine as a parasympathomimetic. Therefore, it
can be used to counteract atropine poisoning (Nickalls and Nickalls 1988). There are a
number of other plant-derived acetylcholine esterase inhibitors, including galanthamine,
which has recently been approved for use in treatment of the symptoms of Alzheimer’s
disease. Infamously, chemical weapons, such as tabun and sarin, are synthetic cholinesterase inhibitors, which act in a quasi-irreversible fashion. Moreover, a number of acetylcholine esterase inhibitors have been used as pesticides, including organophosphates.
The acetylcholine receptor agonist muscarine is, in contrast to acetylcholine, not
degradable by acetylcholine esterase. Therefore, it has a strong and lasting effect, whereby
the main symptoms of muscarine poisoning (from mushrooms including Clitocybe and
Inocybe species) concern the parasympathetic nervous system. They include strong contraction of the pupils, heavy perspiration, nausea and others. Muscarine is also neurotoxic, and it can lead to heart paralysis due to the effects on M2 receptors in pacemaker
cells as described above. Furthermore, the pyridine alkaloid arecoline is another acetylcholine receptor agonist. Its structure is based on nicotinic acid and it is not specific for
MAchRs but also binds to the NAchR.
Atropine, the alkaloid from Atropa belladonna, Datura stramonium and Mandragora
officinarum, is an antagonist of MAchRs and is therefore a parasympathicolyticum. This
makes it an antidote of muscarine and acetylcholine esterase inhibitors, including the
chemicals used in warfare and pesticides mentioned above. Therefore, it is always part of
medical emergency gear. Medically, it is used to increase the heart rate in some conditions,
dilate pupils, reduce salivary gland secretion (for instance during surgery) and relax intestines. Obviously, agonists of the MAchRs and inhibitors of acetylcholine esterase counteract atropine poisoning. Further plant-derived antagonists of MAchRs include the tropane
alkaloids scopolamine and hyoscyamine.
5.2 Adrenergic Receptors: Reserpine and Ephedrine
Adrenergic receptors were the first to be described as GPCRs (see 7 Chap. 1). Especially
the β2-adrenoreceptor has served as a model for the pharmacology of GPCRs. It was the
first to be cloned and also the first one to reveal the molecular structure of GPCRs (Dixon
et al. 1986; Rasmussen et al. 2007). Adrenergic receptors are present on target organs of
the sympathetic nervous system (see . Fig. 5.1). These include smooth muscles of blood
vessels and bronchia, the heart, and organs such as the urinary bladder, gastrointestinal
Box 5.1 Allosteric Regulator
Allosteric regulators are compounds that target an enzyme or receptor at a site outside the substrate- or ligand-binding pocket. In this way they regulate the activity of the target molecule indirectly. Positive allosteric regulators increase the activity or ligand binding, and negative allosteric
regulators diminish it.
5.2 · Adrenergic Receptors: Reserpine and Ephedrine
5
Acetylcholine is degraded by acetylcholine esterase. Inhibitors of acetylcholine esterase
thus prolong and increase the synaptic transmission by acetylcholine. Physostigmine, an
indole alkaloid of the Calabar bean (Physostigma venenosum), is a reversible acetylcholine
esterase inhibitor. It mainly targets the acetylcholine in postganglionic parasympathetic
neurons and thus indirectly acts like muscarine as a parasympathomimetic. Therefore, it
can be used to counteract atropine poisoning (Nickalls and Nickalls 1988). There are a
number of other plant-derived acetylcholine esterase inhibitors, including galanthamine,
which has recently been approved for use in treatment of the symptoms of Alzheimer’s
disease. Infamously, chemical weapons, such as tabun and sarin, are synthetic cholinesterase inhibitors, which act in a quasi-irreversible fashion. Moreover, a number of acetylcholine esterase inhibitors have been used as pesticides, including organophosphates.
The acetylcholine receptor agonist muscarine is, in contrast to acetylcholine, not
degradable by acetylcholine esterase. Therefore, it has a strong and lasting effect, whereby
the main symptoms of muscarine poisoning (from mushrooms including Clitocybe and
Inocybe species) concern the parasympathetic nervous system. They include strong contraction of the pupils, heavy perspiration, nausea and others. Muscarine is also neurotoxic, and it can lead to heart paralysis due to the effects on M2 receptors in pacemaker
cells as described above. Furthermore, the pyridine alkaloid arecoline is another acetylcholine receptor agonist. Its structure is based on nicotinic acid and it is not specific for
MAchRs but also binds to the NAchR.
Atropine, the alkaloid from Atropa belladonna, Datura stramonium and Mandragora
officinarum, is an antagonist of MAchRs and is therefore a parasympathicolyticum. This
makes it an antidote of muscarine and acetylcholine esterase inhibitors, including the
chemicals used in warfare and pesticides mentioned above. Therefore, it is always part of
medical emergency gear. Medically, it is used to increase the heart rate in some conditions,
dilate pupils, reduce salivary gland secretion (for instance during surgery) and relax intestines. Obviously, agonists of the MAchRs and inhibitors of acetylcholine esterase counteract atropine poisoning. Further plant-derived antagonists of MAchRs include the tropane
alkaloids scopolamine and hyoscyamine.
5.2 Adrenergic Receptors: Reserpine and Ephedrine
Adrenergic receptors were the first to be described as GPCRs (see 7 Chap. 1). Especially
the β2-adrenoreceptor has served as a model for the pharmacology of GPCRs. It was the
first to be cloned and also the first one to reveal the molecular structure of GPCRs (Dixon
et al. 1986; Rasmussen et al. 2007). Adrenergic receptors are present on target organs of
the sympathetic nervous system (see . Fig. 5.1). These include smooth muscles of blood
vessels and bronchia, the heart, and organs such as the urinary bladder, gastrointestinal
Box 5.1 Allosteric Regulator
Allosteric regulators are compounds that target an enzyme or receptor at a site outside the substrate- or ligand-binding pocket. In this way they regulate the activity of the target molecule indirectly. Positive allosteric regulators increase the activity or ligand binding, and negative allosteric
regulators diminish it.
5.2 · Adrenergic Receptors: Reserpine and Ephedrine