Nicotinic agonist
Encyclopedia
A nicotinic agonist is a drug which enhances the action at the nicotinic acetylcholine receptor
(nAChR).
Examples include:
Nicotine has been known for centuries for its intoxicating effect. It was first isolated in 1828 from the tobacco plant
by German chemists, Posselt and Reimann.
The discovery of positive effects from nicotine on animal memory was discovered by in vivo
researches in the middle of the 1980s. Those researches led to a new era in studies of nicotinic acetylcholine receptor (nAChR) and their stimulation but until then the focus had mainly been on nicotine addiction.
The development of nAChR agonists began in the early 1990s after the discovery of nicotine’s positive effects. Some research showed a possible therapy option in preclinical researches. ABT-418
was one of the first in a series of nAChR agonists and it was designed by Abbott Labs
. ABT-418 showed significant increase of delayed matching-to-sample (DMTS) performance in matured Macaque apes
of different species and sex. ABT-418 has also been examined as a possible treatment to Alzheimer’s disease, Parkinson’s disease and attention-deficit hyperactivity disorder: those experiments showed positive outcomes.
One of the first nAChR active compounds, besides nicotine, that was marketed as a drug was galantamine
, a plant alkaloid
that works as a weak cholinesterase
inhibitor (IC50=5µM) as well as an allosteric sensitizer for nAChRs (EC50=50 nM).
nicotinic cholinergic signals are extended throughout the system, where the neurotransmitter acetylcholine (ACh) plays a key role in activating ligand-gated ion channel
s.
The cholinergic system is a vital nervous pathway, where cholinergic neurons synthesize, store and release the neurotransmitter ACh. The main receptors that convert the ACh messages are the cholinergic muscarinic acetylcholine receptors, neuronal and muscular nAChRs. When looking back at evolutionary history, ACh is considered to be the oldest transmitter molecule and became present before the nervous cell. In the nervous system cholinergic stimulation mediated through nAChRs controls pathways such as release of transmitters and cell sensitivity, which can influence physiological activity including sleep, anxiety, processing of pain and cognitive functions.
receptors found in the central nervous system (CNS), peripheral nervous systems (PNS) and skeletal muscles, these receptors are ligand-gated ion channels with binding sites for acetylcholine and other molecules. When ACh or other agonists bind to the receptors it stabilizes the open state of the ion channel allowing influx of cations such as potassium, calcium and sodium ions. The nAChRs are made up by different subunits which determine the quaternary structure
of the receptor, those subunits are α subunits (α1–10), β subunits (β1–4), one δ subunits, one γ subunit and one ε subunit. nAChRs can be either heteromer
ic or homomeric
. The heteromeric receptors found in the central nervous system are made up by 2 α and 3 β subunits with the binding site at the interface of α and the adjacent subunit, these receptor contain 2 binding sites per receptor and have different affinity for chemicals based on the composition of subunits. Both binding sites work together and thus, both sites need to be occupied with a nAChR agonist so that channel activation can take place. nAChRs containing α2–α6 and β2–β4 subunits have been shown to have higher affinity for ACh than other receptors. Homomeric receptors contain 5 identical subunits, they have 5 binding sites located at the interface between two adjacent subunits. In the year 2000 two homomeric receptors had been identified in humans, the α7 and α8 receptors.
The ACh binding site of nAChR is made up by six loops, termed A–F. The A, B and C loops of the binding site are the principal components of the binding site, they are part of the α subunit. The adjacent subunit to the α subunit (γ, δ, ε or β) contains the D, E and F loops.
. The α7 are not believed to have as much affinity for nicotine as the heteromeric receptor but instead they have shown more affinity for alpha bungarotoxin which is a nicotinic antagonist found in venom of some snakes. Targeting of α7 receptors is therefore thought to be useful in treatment of Alzheimer’s disease and schizophrenia.
on skeletal muscles. Two different receptors have been found, one of whom has primarily been found in adults contains two α1 subunits, one β1, one ε and one δ, the other one has been found in fetuses and contains γ subunit instead of the ε subunit. The nAChRs take part in the depolarization
of the muscular endplate by increasing cation permeability leading to contraction of skeletal muscles. The nAChRs found in the skeletal muscle system have two ACh binding sites one of whom is found at the interface between α1 and δ subunits while the other one is found at the interface between α1 and γ or ε subunits. Among nAChR agonists designed specifically for the neuromuscular system are nerve gases and other poisons designed for quick kill either of humans and other animals or insects.
. Agonists, e.g. nicotine, can however act as depolarizing agents when encountered to nAChRs for some time (seconds or minutes, depending on concentration and nAChR subtype), chronic exposure to agonist can also lead to long lasting functional deactivation because of rapid and persistent desensitization. Partial nAChR agonists have been studied since they seem to be helpful in smoking cessation. The partial agonists are believed to bind to the nAChRs and stimulate the release of dopamine
in smaller portions than the agonists and therefore compensate for the absence of nicotine.
The lack of specificity among some of the nicotinic agonists is well known and is a potential problem when using them to treat illnesses that require targeting a specific subtype of nAChRs. Among these nonspecific agonists are for example ACh, nicotine and epibatidine
that all target more than one subtype of nAChRs.
The development of nAChR agonist pharmacophore
started in 1970 when it was proposed that the binding of the agonists to a receptor was dependant on a positively charged nitrogen atom and a hydrogen bond forming from carbonyl oxygen atom in acetylcholine or a nitrogen atom in (S)-nicotine. Since then it has been shown that a cationic center, atoms that are electronegative and able to form hydrogen bonds along with the center of the pyridine ring in (S)-nicotine are favorable. Stereochemistry
is a part of the pharmacophore as is clearly seen with (S)- and (R)- nicotine where the (S)-enantiomer
is 10-100 times more potent. The azabicyclic ring of epibatidine is another example of favorable steric interactions to the receptors. It has been suggested that a specific internitrogen distance, N+-N, is important for agonist affinity but debate has arisen over its influence. A newer theory is that a distance of 7-8 Å between points that complement the protonated nitrogen atom and hydrogen bond acceptor will enhance the potency. Low electronic density
close to the protonated nitrogen and higher electron density close to the pyridine ring is favored in protonated nicotine ligand
s containing pyridine ring. In later years researchers have taken more interest in the α7 and α4β2 subtype receptors in drug development to treat nicotine dependence and cognitive impairment such as Alzheimer’s.
> pyrantel
> nicotine > coniine
> tubocurare
> lobeline
, where anatoxin had the highest activity efficacy and tubocurare the lowest. Acetylcholine on the other hand induced a much longer opening time of the receptor though anatoxin is more potent. The results suggest that anatoxin derivatives would be helpful in understanding structure-activity relationships (SAR) for muscle nAChRs.
Succinylcholine chloride
, which is a drug that’s already on the market, is a bischoline ester and a short acting muscle relaxant. Bischoline esters are compounds that can act as a competitive agonist on muscle type nAChRs and have been used in SAR studies. In a Torpedo
(α1)2β1δγ nAChR model it was demonstrated that the potency of bischoline ester agonists is dependant on the chain length as potency increases with longer chains. Efficacy seems to be independent of chain length since the highest efficacy is seen in bischoline esters with four to seven methylene
groups and is lower for both fewer methylene groups and more.
profiles and are selective of α7 nAChRs over α1, α3 and α4β2 nAChRs. Structure activity relationships for these compounds have been proposed.
The optimal pharmacophore of α7 nAChR agonist is made of three parts. There is a basic moiety connected to a carbon chain linked to an aromatic moiety by an amide bridge. The amide bridge can be inverted without affecting the potency of the agonist. A biaryl
group shows more potency than a monoaryl group as the aromatic moiety and substitution at position 2 on the later aryl group will further increase the potency. Potency is higher for agonists with H+ donor/acceptor on the later aryl group on the biaryl group. A high number of hydrogen bond
acceptors could decrease permeability across the blood-brain barrier
(BBB) do to the polar surface area and needs to be taken into account when designing agonists to target α7 nAChRs.
Various cyclic amine
groups can act as the basic moiety and potency stays relatively unchanged for example aryl piperazine
, piperidine
and morpholine
. An acyclic tertiary amine is tolerated as the basic moiety but larger steric groups are less tolerated.
Many derivatives of quinuclidine
such as quinuclidine amide are known to be α7 nAChR agonists. SAR studies for quinuclidine amide have identified factors that are affecting the potency and affinity of these agonists. Para substitution on the quinuclidine ring and the 3-(R) configuration in the stereochemistry is favored. Enhanced activity is observed when a 5 membered ring is fused to aromatic moiety. Further enhancement is seen when the fused ring is able to supply electron resonance to the amide carbonyl whereas the activity will diminish when the fused ring contains a hydrogen bond donating atom. The rigidity of quinuclidine and the orthogonal orientation of the nitrogen bridge in relations to the amide carbonyl group is presumed important for the optimal binding. The stability of some of the more potent quinuclidine amide derivatives in rat in vitro models have been low however by adding a methyl group to position 2 on the quinuclidine ring the stability has increased greatly.
, schizophrenia
, attention-deficit hyperactivity disorder
(ADHD) and nicotine addiction.
Nicotinic acetylcholine receptors are receptors found in the central nervous system
, the peripheral nervous system
s and skeletal muscles. They are ligand-gated ion channels with binding sites for acetylcholine
as well as other agonists. When agonists bind to a receptor it stabilizes the open state of the ion channel allowing influx of cations.
In 2009 there were at least five drugs on the market that affect the nicotinic acetylcholine receptors.
Other nicotinic agonists, albeit generally with limited clinical use, include:
Targacept has four drug candidates that are in clinical trials; AZD3480 (TC-1734) for ADHD which is currently in phase II clinical trials and AZD1446 (TC-6683) for Alzheimers disease in collaboration with AstraZeneca
, TC-5619
for cognitive dysfunction
s in schizophrenia and TC-5214
as an augmentation treatment for major depressive disorder (MDD) in subjects who did not respond adequately to first-line treatment with citalopram hydrobromide.
Memory pharmaceuticals with its partner Roche has one drug candidate, MEM 3454 (RG3487), a partial agonist of the nicotinic alpha-7 receptor
, for Alzheimers disease.
Abbott Laboratories in partnership with NeuroSearch have two drug candidates in clinical trials, ABT-894, a selective α4β2 nicotine receptor agonist, for ADHD and ABT-560, a neuronal nicotinic receptor modulator, which was selected by Abbott in 2006 as a new development candidate for cognitive dysfunctions.
EnVivo pharmaceuticals has one drug candidate in clinical trials, EVP-6124, a selective α7 nicotine receptor agonist for Alzheimer’s disease and schizophrenia and one follow-up compound, EVP-4473, that has successfully completed pre-clinical development
.
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
(nAChR).
Examples include:
- nicotineNicotineNicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
(by definition—the "nicotinic acetylcholine receptor" is named for its affinity for nicotine) - acetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, the endogenous agonist of nAChRs - cholineCholineCholine is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
- epibatidineEpibatidineEpibatidine is an alkaloid found on the skin of the endangered Ecuadorian frog, Epipedobates tricolor. These frogs, like other poison dart frogs, are best known for their ability to sequester poisons from their prey and secrete these poisons onto their backs. Many Amerindian tribes would swipe the...
- lobelineLobelineLobeline is a natural alkaloid found in "Indian tobacco" , "Devil's tobacco" , "cardinal flower" , "great lobelia" , and Hippobroma longiflora...
- varenicline
History
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...
by German chemists, Posselt and Reimann.
The discovery of positive effects from nicotine on animal memory was discovered by in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
researches in the middle of the 1980s. Those researches led to a new era in studies of nicotinic acetylcholine receptor (nAChR) and their stimulation but until then the focus had mainly been on nicotine addiction.
The development of nAChR agonists began in the early 1990s after the discovery of nicotine’s positive effects. Some research showed a possible therapy option in preclinical researches. ABT-418
ABT-418
ABT-418 is a drug developed by Abbott, which acts as an agonist at neural nicotinic acetylcholine receptors. It binds with high affinity to the α4β2, α2β2 and α7 subtypes, but not to the α3β4 subtype. It has nootropic, neuroprotective and anxiolytic effects, and has been researched for treatment of...
was one of the first in a series of nAChR agonists and it was designed by Abbott Labs
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
. ABT-418 showed significant increase of delayed matching-to-sample (DMTS) performance in matured Macaque apes
Macaque
The macaques constitute a genus of Old World monkeys of the subfamily Cercopithecinae. - Description :Aside from humans , the macaques are the most widespread primate genus, ranging from Japan to Afghanistan and, in the case of the barbary macaque, to North Africa...
of different species and sex. ABT-418 has also been examined as a possible treatment to Alzheimer’s disease, Parkinson’s disease and attention-deficit hyperactivity disorder: those experiments showed positive outcomes.
One of the first nAChR active compounds, besides nicotine, that was marketed as a drug was galantamine
Galantamine
Galantamine is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of vascular origin...
, a plant alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
that works as a weak cholinesterase
Cholinesterase
In biochemistry, cholinesterase is a family of enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.-Types:...
inhibitor (IC50=5µM) as well as an allosteric sensitizer for nAChRs (EC50=50 nM).
Nicotinic acetylcholine receptors and their signaling system
Signaling system
In the human nervous systemNervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
nicotinic cholinergic signals are extended throughout the system, where the neurotransmitter acetylcholine (ACh) plays a key role in activating ligand-gated ion channel
Ligand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
s.
The cholinergic system is a vital nervous pathway, where cholinergic neurons synthesize, store and release the neurotransmitter ACh. The main receptors that convert the ACh messages are the cholinergic muscarinic acetylcholine receptors, neuronal and muscular nAChRs. When looking back at evolutionary history, ACh is considered to be the oldest transmitter molecule and became present before the nervous cell. In the nervous system cholinergic stimulation mediated through nAChRs controls pathways such as release of transmitters and cell sensitivity, which can influence physiological activity including sleep, anxiety, processing of pain and cognitive functions.
Nicotinic acetylcholine receptors
nAChRs are cholinergicCholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
receptors found in the central nervous system (CNS), peripheral nervous systems (PNS) and skeletal muscles, these receptors are ligand-gated ion channels with binding sites for acetylcholine and other molecules. When ACh or other agonists bind to the receptors it stabilizes the open state of the ion channel allowing influx of cations such as potassium, calcium and sodium ions. The nAChRs are made up by different subunits which determine the quaternary structure
Quaternary structure
In biochemistry, quaternary structure is the arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex.-Description and examples:...
of the receptor, those subunits are α subunits (α1–10), β subunits (β1–4), one δ subunits, one γ subunit and one ε subunit. nAChRs can be either heteromer
Heteromer
-Pharmacology:* Ligand-gated ion channels such as the nicotinic acetylcholine receptor and GABAA receptor are composed of five subunits arranged around a central pore that opens to allow ions to pass through. There are a large number of different subunits available, which can come together in a...
ic or homomeric
Homomeric
A homomeric substance is one which is made out of any number of identical products or molecules.e.g. A homomeric peptide = glutathione A peptide which is made up of only a single type of amino acid subunit; e.g., alanylalanylalanine.ALA-ALA-ALA...
. The heteromeric receptors found in the central nervous system are made up by 2 α and 3 β subunits with the binding site at the interface of α and the adjacent subunit, these receptor contain 2 binding sites per receptor and have different affinity for chemicals based on the composition of subunits. Both binding sites work together and thus, both sites need to be occupied with a nAChR agonist so that channel activation can take place. nAChRs containing α2–α6 and β2–β4 subunits have been shown to have higher affinity for ACh than other receptors. Homomeric receptors contain 5 identical subunits, they have 5 binding sites located at the interface between two adjacent subunits. In the year 2000 two homomeric receptors had been identified in humans, the α7 and α8 receptors.
Binding site
There are two binding sites on heteromeric nAChRs, in order to stabilize the open form of nAChRs both binding sites must be occupied by agonist, such as nicotine or ACh.The ACh binding site of nAChR is made up by six loops, termed A–F. The A, B and C loops of the binding site are the principal components of the binding site, they are part of the α subunit. The adjacent subunit to the α subunit (γ, δ, ε or β) contains the D, E and F loops.
Mechanism of Action
α4β2 receptor agonists
α4β2 nAChRs contain two α4 subunits and three β2 subunits, therefore it has two binding sites for ACh and other agonists. α4β2 nAChRs account for approximately 90% of the nAChRs in the human brain and when chronically exposed to nicotine or other nicotine agonists leads to increase in density of α4β2 receptors which is the opposite of what usually happens when other receptors are chronically exposed to their agonists. The α4β2 receptor has been widely studied in regards to Alzheimer’s disease as well as for nicotine dependence and in 2009 several drugs are on the market that target the α4β2 nAChR specifically.α7 receptor agonists
α7 receptors are homomeric neuronal acetylcholine receptors consisting of five α7 subunits and has 5 ACh binding sites. Abnormality in the α7 receptors expression have been reported to influence progression of diseases such as Alzheimer’s disease and schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. The α7 are not believed to have as much affinity for nicotine as the heteromeric receptor but instead they have shown more affinity for alpha bungarotoxin which is a nicotinic antagonist found in venom of some snakes. Targeting of α7 receptors is therefore thought to be useful in treatment of Alzheimer’s disease and schizophrenia.
Muscle type receptor agonists
nAChR are found in the neuromuscular junctionNeuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
on skeletal muscles. Two different receptors have been found, one of whom has primarily been found in adults contains two α1 subunits, one β1, one ε and one δ, the other one has been found in fetuses and contains γ subunit instead of the ε subunit. The nAChRs take part in the depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
of the muscular endplate by increasing cation permeability leading to contraction of skeletal muscles. The nAChRs found in the skeletal muscle system have two ACh binding sites one of whom is found at the interface between α1 and δ subunits while the other one is found at the interface between α1 and γ or ε subunits. Among nAChR agonists designed specifically for the neuromuscular system are nerve gases and other poisons designed for quick kill either of humans and other animals or insects.
Binding
ACh binds to nAChR because of charge difference between the molecule and the surface of the receptor. When binding to nAChR ACh fits into a binding pocket shaped by loops A, B and C which belong to α subunit and the adjacent subunit. When ACh is fitted into the binding pocket the loops of the nAChR undergo movement that leads to a coordination of the ACh molecule in the pocket enhancing the chemical bonds between the molecule and the receptor. After movement of the loops that belong to α subunit it’s sometimes possible for the ACh molecule to form a bond, e.g. salt bridge, to the adjacent subunit enhancing the bonds between the receptor and ACh even further.Drug design
Drugs that influence nAChRs can be agonists, partial agonists or antagonistsReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
. Agonists, e.g. nicotine, can however act as depolarizing agents when encountered to nAChRs for some time (seconds or minutes, depending on concentration and nAChR subtype), chronic exposure to agonist can also lead to long lasting functional deactivation because of rapid and persistent desensitization. Partial nAChR agonists have been studied since they seem to be helpful in smoking cessation. The partial agonists are believed to bind to the nAChRs and stimulate the release of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in smaller portions than the agonists and therefore compensate for the absence of nicotine.
The lack of specificity among some of the nicotinic agonists is well known and is a potential problem when using them to treat illnesses that require targeting a specific subtype of nAChRs. Among these nonspecific agonists are for example ACh, nicotine and epibatidine
Epibatidine
Epibatidine is an alkaloid found on the skin of the endangered Ecuadorian frog, Epipedobates tricolor. These frogs, like other poison dart frogs, are best known for their ability to sequester poisons from their prey and secrete these poisons onto their backs. Many Amerindian tribes would swipe the...
that all target more than one subtype of nAChRs.
Pharmacophore
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
started in 1970 when it was proposed that the binding of the agonists to a receptor was dependant on a positively charged nitrogen atom and a hydrogen bond forming from carbonyl oxygen atom in acetylcholine or a nitrogen atom in (S)-nicotine. Since then it has been shown that a cationic center, atoms that are electronegative and able to form hydrogen bonds along with the center of the pyridine ring in (S)-nicotine are favorable. Stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
is a part of the pharmacophore as is clearly seen with (S)- and (R)- nicotine where the (S)-enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
is 10-100 times more potent. The azabicyclic ring of epibatidine is another example of favorable steric interactions to the receptors. It has been suggested that a specific internitrogen distance, N+-N, is important for agonist affinity but debate has arisen over its influence. A newer theory is that a distance of 7-8 Å between points that complement the protonated nitrogen atom and hydrogen bond acceptor will enhance the potency. Low electronic density
Electronic density
In quantum mechanics, and in particular quantum chemistry, the electronic density is a measure of the probability of an electron occupying an infinitesimal element of space surrounding any given point. It is a scalar quantity depending upon three spatial variables and is typically denoted as either...
close to the protonated nitrogen and higher electron density close to the pyridine ring is favored in protonated nicotine ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s containing pyridine ring. In later years researchers have taken more interest in the α7 and α4β2 subtype receptors in drug development to treat nicotine dependence and cognitive impairment such as Alzheimer’s.
Structure-activity relationships: Muscle nAChR agonists
Various models have been run where the affinity of nAChR agonists to the receptor subtype are tested to help identify the molecules, groups and steric conformation that are vital to greater affinity. By using a nAChR muscle receptor subtype (α1)2β1δγ model the following results were obtained: anatoxin > epibatidine > acetylcholine > DMPP >> cytisineCytisine
Cytisine, also known as baphitoxine and sophorine, is a pyridine-like alkaloid. In medical use, it improves the rate of smoking cessation. It is less effective but much cheaper than similar products. Its structure is similar to nicotine and has similar pharmacological effects...
> pyrantel
Pyrantel
Pyrantel is an antinematodal thiophene. It is often prescribed by veterinarians to treat and prevent the occurrence of intestinal parasites in small animal pets.-Mechanism of Action:Pyrantel is a nicotinic receptor agonist...
> nicotine > coniine
Coniine
Coniine is a poisonous alkaloid found in poison hemlock and the yellow pitcher plant, and contributes to hemlock's fetid smell. It is a neurotoxin which disrupts the peripheral nervous system. It is toxic to humans and all classes of livestock; less than 0.2g is fatal to humans, with death caused...
> tubocurare
Tubocurarine
Tubocurarine is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation...
> lobeline
Lobeline
Lobeline is a natural alkaloid found in "Indian tobacco" , "Devil's tobacco" , "cardinal flower" , "great lobelia" , and Hippobroma longiflora...
, where anatoxin had the highest activity efficacy and tubocurare the lowest. Acetylcholine on the other hand induced a much longer opening time of the receptor though anatoxin is more potent. The results suggest that anatoxin derivatives would be helpful in understanding structure-activity relationships (SAR) for muscle nAChRs.
Succinylcholine chloride
Suxamethonium chloride
Suxamethonium chloride , also known as suxamethonium or succinylcholine, is a paralytic drug used to induce muscle relaxation and short-term paralysis, usually to facilitate tracheal intubation. Suxamethonium is sold under the trade names Anectine, Quelicin, and Scoline. It is used as a paralytic...
, which is a drug that’s already on the market, is a bischoline ester and a short acting muscle relaxant. Bischoline esters are compounds that can act as a competitive agonist on muscle type nAChRs and have been used in SAR studies. In a Torpedo
Electric ray
The electric rays are a group of rays, flattened cartilaginous fish with enlarged pectoral fins, comprising the order Torpediniformes. They are known for being capable of producing an electric discharge, ranging from as little as 8 volts up to 220 volts depending on species, used to stun prey and...
(α1)2β1δγ nAChR model it was demonstrated that the potency of bischoline ester agonists is dependant on the chain length as potency increases with longer chains. Efficacy seems to be independent of chain length since the highest efficacy is seen in bischoline esters with four to seven methylene
Methylene
Methylene is a chemical species in which a carbon atom is bonded to two hydrogen atoms. Three different possibilities present themselves:* the -CH2- substituent group: e.g., dichloromethane ....
groups and is lower for both fewer methylene groups and more.
Structure-activity relationships: α4β2 nAChR agonists
Combination of structural elements of ACh and nicotine as well as reducing the conformational flexibility by using a cyclopropane ring has led to the discovery of potent and selective α4β2 nAChR ligands. The modulation of three structural elements, the linker, substitution on the amino group and the pyridine ring can be used to determine the influence on potency and selectivity of the ligands. Factors that decrease the binding are steric hindrance on the amino group and linkers that are saturated/unsaturated carbon chains. Short-chained ether linkers are preferred. Beneficial effects on the binding is seen with substitution on the pyridine ring both mono- and disubstitution with halogens among other groups. Substitution on the amino group with three different amides increased the binding affinity where methylamide had the highest binding. Lower binding in the other substituted amides was explained by steric hindrance or lack of a methyl group resulting in loss of hydrophobic interaction. Stereochemistry of pyridine nitrogen and/or the pyridine ring and its stereoelectronic effects has a subtle beneficial effect on the binding to the α4β2 nAChR. Thus it was shown that a pyridyl ether ligand with bromo substitution on the pyridine and metylatedamide on the amino group had the highest potency.Structure-activity relationships: α7 nAChR agonists
The search for selective and potent α7 nAChR agonists has produced a series of compounds that have good potential as drug candidates. One such search produced SEN12333/WAY-317538 among other compounds that have desirable pharmacokineticPharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
profiles and are selective of α7 nAChRs over α1, α3 and α4β2 nAChRs. Structure activity relationships for these compounds have been proposed.
The optimal pharmacophore of α7 nAChR agonist is made of three parts. There is a basic moiety connected to a carbon chain linked to an aromatic moiety by an amide bridge. The amide bridge can be inverted without affecting the potency of the agonist. A biaryl
Aryl
In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....
group shows more potency than a monoaryl group as the aromatic moiety and substitution at position 2 on the later aryl group will further increase the potency. Potency is higher for agonists with H+ donor/acceptor on the later aryl group on the biaryl group. A high number of hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
acceptors could decrease permeability across the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
(BBB) do to the polar surface area and needs to be taken into account when designing agonists to target α7 nAChRs.
Various cyclic amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
groups can act as the basic moiety and potency stays relatively unchanged for example aryl piperazine
Piperazine
Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
, piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
and morpholine
Morpholine
Morpholine is an organic chemical compound having the chemical formula O2NH. This heterocycle, pictured at right, features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium...
. An acyclic tertiary amine is tolerated as the basic moiety but larger steric groups are less tolerated.
Many derivatives of quinuclidine
Quinuclidine
Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair...
such as quinuclidine amide are known to be α7 nAChR agonists. SAR studies for quinuclidine amide have identified factors that are affecting the potency and affinity of these agonists. Para substitution on the quinuclidine ring and the 3-(R) configuration in the stereochemistry is favored. Enhanced activity is observed when a 5 membered ring is fused to aromatic moiety. Further enhancement is seen when the fused ring is able to supply electron resonance to the amide carbonyl whereas the activity will diminish when the fused ring contains a hydrogen bond donating atom. The rigidity of quinuclidine and the orthogonal orientation of the nitrogen bridge in relations to the amide carbonyl group is presumed important for the optimal binding. The stability of some of the more potent quinuclidine amide derivatives in rat in vitro models have been low however by adding a methyl group to position 2 on the quinuclidine ring the stability has increased greatly.
Drug development
The development of nicotinic acetylcholine receptor agonists began in the early 1990s after the discovery of nicotine’s positive effects on animal memory. The development of nicotinic acetylcholine receptor agonists has come a long way since then. The nicotinic acetylcholine receptor agonist are gaining increasing attention as drug candidates for multiple central nervous system disorders such as Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, attention-deficit hyperactivity disorder
Attention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
(ADHD) and nicotine addiction.
Nicotinic acetylcholine receptors are receptors found in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
s and skeletal muscles. They are ligand-gated ion channels with binding sites for acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
as well as other agonists. When agonists bind to a receptor it stabilizes the open state of the ion channel allowing influx of cations.
In 2009 there were at least five drugs on the market that affect the nicotinic acetylcholine receptors.
| Quinuclidine Carbamates | Quinuclidine Amides | Quinuclidine Ethers |
Products of nicotinic agonist
| Active ingredient | Product name | Chemical name | Pharmaceutical form | Pharmacodynamic properties | Therapeutic use | Structure |
|---|---|---|---|---|---|---|
| Varenicline tartrate | Champix, Chantix | 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine | Film coated tablet | Partial agonist of the nicotinic acetylcholine receptor, subtype α4β2 | Treatment of tobacco dependence | |
| Galantamine hydrobromide Galantamine Galantamine is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of vascular origin... |
Reminyl, Nivalin, Razadyne and Razadyn ER | 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]-benzazepin-6-ol | Sustained release capsule, film coated tablet , oral solution | Cholinesterasa inhibitor and a noncompetative agonist of the nicotinic acetylcholine receptor | Treatment of dementia caused by Alzheimer's disease | |
| Nicotine Nicotine Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves... |
Nicorette, Nicotinell, Niquitin, Boots NicAssist, Commit, Habitrol, Nicoderm CQ, Nicotrol, Thrive | 3-[(2S)-1-methylpyrrolidine-2-yl]pyridine | Transdermal patch, gum, inhaler, nasal spray, lozenge, microtab | Agonist of the nicotinic receptor, both Ganglion type Ganglion type nicotinic receptor The ganglion type nicotinic receptor is a type of nicotinic acetylcholine receptor, consisting of the subunit combination 23.It is located in the autonomic ganglia, where activation yields EPSP, mainly by increased Na+ and K+ permeability.... and α4β2 |
Treatment of tobacco dependence | |
| Carbachol Carbachol Carbachol , also known as carbamylcholine, is a drug that binds and activates the acetylcholine receptor. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery... |
Miostat | 2-[(aminocarbonyl)oxy]-N,N,N-trimethylethanaminium | Intraocular solution | Cholinergic agonist | Treatment of glaucoma |  |
| Suxamethonium chloride Suxamethonium chloride Suxamethonium chloride , also known as suxamethonium or succinylcholine, is a paralytic drug used to induce muscle relaxation and short-term paralysis, usually to facilitate tracheal intubation. Suxamethonium is sold under the trade names Anectine, Quelicin, and Scoline. It is used as a paralytic... (Succinylcholine chloride) |
Anectine, Quelicin Suxamethonium Chloride | 2,2'-[(1,4-dioxobutane-1,4-diyl)bis(oxy)]bis(N,N,N-trimethylethanaminium) | Intravenous or intramuscular injection | Depolarizing neuromuscular blocking agent | Short acting muscle relaxant | |
| Epibatidine Epibatidine Epibatidine is an alkaloid found on the skin of the endangered Ecuadorian frog, Epipedobates tricolor. These frogs, like other poison dart frogs, are best known for their ability to sequester poisons from their prey and secrete these poisons onto their backs. Many Amerindian tribes would swipe the... |
Not listed | 2-(6-chloropyridin-3-yl)-7-azabicyclo[2.2.1]heptane | Not listed | Agonist of the nicotinic acetylcholine receptor | Not used as a drug |  |
Other nicotinic agonists, albeit generally with limited clinical use, include:
- lobelineLobelineLobeline is a natural alkaloid found in "Indian tobacco" , "Devil's tobacco" , "cardinal flower" , "great lobelia" , and Hippobroma longiflora...
, an agonist on Ganglion type nicotinic receptorGanglion type nicotinic receptorThe ganglion type nicotinic receptor is a type of nicotinic acetylcholine receptor, consisting of the subunit combination 23.It is located in the autonomic ganglia, where activation yields EPSP, mainly by increased Na+ and K+ permeability....
s and also affects sensory nerve terminals - epibatidineEpibatidineEpibatidine is an alkaloid found on the skin of the endangered Ecuadorian frog, Epipedobates tricolor. These frogs, like other poison dart frogs, are best known for their ability to sequester poisons from their prey and secrete these poisons onto their backs. Many Amerindian tribes would swipe the...
, and agonist on Ganglion typeGanglion type nicotinic receptorThe ganglion type nicotinic receptor is a type of nicotinic acetylcholine receptor, consisting of the subunit combination 23.It is located in the autonomic ganglia, where activation yields EPSP, mainly by increased Na+ and K+ permeability....
, α4β2 and α7 receptors. - decamethoniumDecamethoniumDecamethonium is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.- Pharmacology :...
causes depolarization block on muscle typeMuscle type nicotinic receptorThe muscle-type nicotinic receptor is a type of nicotinic acetylcholine receptor, consisting of the subunit combination 2β1δε or 2β1δγ....
receptors, similarly to suxamethonium
Current status
Currently nicotine receptor agonist research and drug designing is aimed for treatment of multiple diseases and disorders of the CNS.Targacept has four drug candidates that are in clinical trials; AZD3480 (TC-1734) for ADHD which is currently in phase II clinical trials and AZD1446 (TC-6683) for Alzheimers disease in collaboration with AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
, TC-5619
TC-5619
TC-5619 is a drug developed by Targacept that acts as a partial agonist at the α7 subtype of the neural nicotinic acetylcholine receptors. It showed cognitive enhancing effects in animal studies, and is currently being developed through a collaboration between Targacept and AstraZeneca as a...
for cognitive dysfunction
Cognitive dysfunction
Cognitive dysfunction is defined as unusually poor mental function, associated with confusion, forgetfulness and difficulty concentrating...
s in schizophrenia and TC-5214
Mecamylamine
Mecamylamine is a nonselective and noncompetitive antagonist of the nicotinic acetylcholine receptors that was introduced in the 1950s as an antihypertensive agent.- Uses :...
as an augmentation treatment for major depressive disorder (MDD) in subjects who did not respond adequately to first-line treatment with citalopram hydrobromide.
Memory pharmaceuticals with its partner Roche has one drug candidate, MEM 3454 (RG3487), a partial agonist of the nicotinic alpha-7 receptor
Alpha-7 nicotinic receptor
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor, consisting entirely of α7 subunits....
, for Alzheimers disease.
Abbott Laboratories in partnership with NeuroSearch have two drug candidates in clinical trials, ABT-894, a selective α4β2 nicotine receptor agonist, for ADHD and ABT-560, a neuronal nicotinic receptor modulator, which was selected by Abbott in 2006 as a new development candidate for cognitive dysfunctions.
EnVivo pharmaceuticals has one drug candidate in clinical trials, EVP-6124, a selective α7 nicotine receptor agonist for Alzheimer’s disease and schizophrenia and one follow-up compound, EVP-4473, that has successfully completed pre-clinical development
Pre-clinical development
In drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....
.
See also
- Nicotinic acetylcholine receptorNicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
- AgonistAgonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
- Parasympathomimetic drug
- Muscarinic acetylcholine receptorMuscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...