Drug efficiency of cholinergic neuroreceptor

Definition: a neurotransmitter formed in pre- and postganglionic synapses of the parasympathetic nervous system (acetylcholine).

Introduction:

The chemical identity of neurotransmitters is often difficult to determine experimentally. For example, it is easy using an electron microscope to recognize vesicles on the presynaptic side of a synapse, but it may not be easy to determine directly what chemical is packed into them. The difficulties led to many historical controversies over whether a given chemical was or was not clearly established as a transmitter. In an effort to give some structure to the arguments, neurochemists worked out a set of experimentally tractable rules. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:

• There are precursors and/or synthesis enzymes located in the presynaptic side of the synapse.
• The chemical is present in the presynaptic element.
• It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic neuron.
• There are postsynaptic receptors and the chemical is able to bind to them.
• A biochemical mechanism for inactivation is present.

Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced the importance of these rules. A series of experiments that may have taken several years in the 1960s can now be done, with much better precision, in a few months. Thus, it is unusual nowadays for the identification of a chemical as a neurotransmitter to remain controversial for very long periods of time.

Types of neurotransmitters

There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes.

Major neurotransmitters:

• Amino acids: glutamate, aspartate, D-serine, γ-aminobutyric acid (GABA), glycine
• Monoamines and other biogenic amines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, serotonin (SE, 5-HT)
• Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.

In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are "co-released" along with a small-molecule transmitter, but in some cases a peptide is the primary transmitter at a synapse. β-endorphin is a relatively well known example of a peptide neurotransmitter; it engages in highly specific interactions with opioid receptors in the central nervous system.

Single ions, such as synaptically released zinc, are also considered neurotransmitters by some, as are some gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO). These are not classical neurotransmitters by the strictest definition, however, because although they have all been shown experimentally to be released by presynaptic terminals in an activity-dependent way, they are not packaged into vesicles.

By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain. The next most prevalent is GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Even though other transmitters are used in far fewer synapses, they may be very important functionally—the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamine exert their effects primarily on the dopamine system.

The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.

Cholinergic Stimulating Agents:

Acetylcholine is the chemical transmitter for nerves of the parasympathetic, somatic, preganglionic sympathetic, and parts of the central nervous system. Acetylcholine is synthesized by the transfer of an acetyl group from acetyl CoA to choline, a normal constituent of the diet.

Acetylcholine is concentrated in large amounts in presynaptic vesicles, which release their contents into the synapse when voltage-gated calcium channels open in response to membrane depolarization.

Upon interaction with the receptor, acetylcholine produces an influx of sodium through a ligand-gated ion channel which sends the impulse.

After acetylcholine interacts with the cholinergic receptor it is very rapidly hydrolyzed by the enzyme acetylcholinesterase. The hydrolysis reaction is the reverse of the synthesis reaction except that choline and acetic acid are products. The choline is retaken up by the nerve ending where it is reused for synthesis of new molecules of acetylcholine.

Acetylcholine acts on two vastly different classes of receptors - nicotinic receptors (with two subtypes, one at the neuromuscular junction of skeletal muscle, the other within ganglia and the CNS), and muscarinic receptors (widely distributed within both peripheral and central nervous systems). Muscarinic receptors originally were distinguished from nicotinic receptors by the selectivity of the agonists muscarine and nicotine respectively. Notice the similarities in structure for all three of these compounds.

Although there appears to be at least two cholinergic receptor sites, they are similar enough to be considered as one. The acetylcholine interacts with the receptor site through ionic attraction of the positive nitrogen, polar attraction of the ester group, and through hydrophobic interactions with the methyl groups.

Stimulation:

Stimulation of cholinergic nerves is achieved either directly or indirectly. Direct acting agents (agonists) activate the receptor site by mimicking the effects of acetylcholine. Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing (inactivating) acetylcholine at the receptor site. This inhibition permits the buildup of acetylcholine and results in more intensive and prolonged activation of the receptor site. The effects of cholinergic stimulation include: vasodilation of blood vessels; slower heart rate; constriction of bronchioles and increased secretion of mucus in the respiratory tract; intestinal cramps; secretion of salvia; sweat and tears; and constriction of eye pupils.

Direct Acting Cholinergic Agents - Agonists:

Direct acting cholinergic agents act as agonists and initiate stimulant type responses at the receptor site. Direct stimulation of acetylcholine receptors is achieved by: Arecholine, Pilocarpine, Urecholine(Betanechol), Carbachol, Choline, Metacholine, Mushrooms (Boletus sp., Clitocybe sp. , Inocybe sp.)

Drugs: Urecholine and philocarpine are direct acting drugs. Urecholine is used to restore parasympathetic tone to smooth muscles of the intestinal tract and bladder following abdominal surgery. Pilocarpine is used to constrict pupils and reduce pressure caused by glaucoma. Pilocarpine contracts the ciliary muscle with causes the iris to be withdrawn. This action permits drainage of the aqueous humor and thus relieves the pressure due to a glaucoma condition.

Cholinergic Poison agents which mimic the structure of acetylcholine include two poisons: muscarine - an alkaloid present in poisonous mushrooms and nicotine from cigarettes.

Muscarinic effects are those of parasympathetic overactivity and include bradycardia, pinpoint pupils, sweating, blurred vision, excessive lacrimation, excessive bronchial secretions, wheezing, dyspnoea, coughing, vomiting, abdominal cramping, diarrhea, and urinary and fecal incontinence.

Nicotine: Nicotinic effects are those of sympathetic overactivity and neuromuscular dysfunction and include tachycardia, hypertension, dilated pupils, muscle fasciculation and muscle weakness.

Accidental ingestion of these poisons may produce death from heart failure unless treated with a suitable antidote. Atropine blocks the receptor site to decrease the stimulant effects produced by the muscarine type poisons, but has no effect on nicotine receptors.

Nicotinic and muscarinic receptors

Neurotransmitters interact with specific receptor molecules (proteins). In the case of acetylcholine, these are nicotinic and muscarinic receptors - so called because they were originally distinguished on the basis of their selectivity to nicotine and muscarine, respectively. Activation of these receptors by released ACh continues the process of signal transmission.  

Most peripheral acetylcholine receptors (AChR ) are nicotinic, such as those on the heart or at the neuromuscular junction, which is why nicotinic antagonists (a drug that blocks nicotinic receptors, such as d-tubocurarine, from the arrow poison, curare) are used as muscle relaxants. Nicotinic agonists (nicotine mimicking drugs), including nicotine (7), have been found to improve attention of Alzheimer patients. Another nicotinic agonist, ABT-418 (8), displays cognition-enhancing properties. 

Scientists are currently investigating novel nicotinic agonists which are selective for particular nicotinic receptor subtypes. A number of such compounds are in clinical development, many of which are less toxic than nicotine. 

Muscarinic receptors are stimulated by muscarine, and blocked by atropine, which is the poison (also known as deadly nightshade) found in the belladonna plant. Muscarinic receptors have been divided into five receptor subtypes. Several synthetic muscarinic agonists have been made, based on the structure of acetylcholine. Research points to the three-membered ring of acetoxycyclopropyl-trimethylammonium iodide having the highest intrinsic activity; the trans-isomer (9) having much higher activity than the cis-isomer. Such information will be important in the development of new drugs.

References

1. A. M. Palmer and P. T. Francis in Principles and practice of geriatric medicine, 4th edn, M. S. J. Pathy, A. J. Sinclair and J. E. Morley (eds), pp59-67. Chichester: John Wiley, 2006.
2. A. M. Palmer, Neurodegeneration, 1995,  5 , 381.
3. A. M. Palmer, Investigational Drugs, 2003,  4 ,  833.
4. N. A. Clarke and P. T. Francis, Expert Rev. Neurother., 2005,  5 , 671.
5. See Memantine website.
6. A. M. Palmer, Trends Pharmacol. Sci., 2002,  23 , 426.