Nicotinic agonist
A nicotinic agonist is a drug that mimics the action of
Examples include
History
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.[2]
The discovery of positive effects from nicotine on animal memory was discovered by in vivo researches in the mid 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.[3][4] 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.[4] ABT-418 showed significant increase of delayed matching-to-sample (DMTS) performance in matured macaque apes of different species and sex.[5] 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.[4]
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).[6]
Nicotinic acetylcholine receptors and their signaling system
Signaling system
In the human
Nicotinic acetylcholine receptors
nAChRs are
Binding site
There are two binding sites on heteromeric nAChRs; to stabilize the open form of nAChRs, both binding sites must be occupied by agonist, such as nicotine or ACh.[11]
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 part of the α subunit and are the principal components of the binding site. The adjacent subunit to the α subunit (γ, δ, ε or β) contains the D, E and F loops.[11]
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
α7 receptor agonists
α7 receptors are homomeric neuronal acetylcholine receptors consisting of five α7 subunits and has five ACh binding sites. Abnormality in the α7 receptors expression have been reported to influence progression of diseases such as Alzheimer's disease and
Muscle type receptor agonists
nAChR are found in the neuromuscular junction on skeletal muscles. Two different receptors have been found, one of which 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.[16] The nAChRs found in the skeletal muscle system have two ACh binding sites, one of which 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 antagonists designed specifically for the neuromuscular system are nerve gases and other poisons designed to quickly kill humans or other animals and insects.[12]
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.[17]
Drug design
Drugs that influence nAChRs can be agonists, partial agonists or antagonists.[1] 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.[18]
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.[19][20]
Pharmacophore
The development of nAChR agonist
Structure-activity relationships
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:
- 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.[22]
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 dependent 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 CH
2 units and is lower for both fewer CH
2 units and more.[23]
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.[24]
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
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.[15]
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.[25]
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.
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[27] | Film coated tablet | Partial agonist of the nicotinic acetylcholine receptor, subtype α4β2[28] | Treatment of tobacco dependence[28] | |
Galantamine hydrobromide | 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[29] | Sustained release capsule, film coated tablet, oral solution | Cholinesterase inhibitor and a noncompetitive agonist of the nicotinic acetylcholine receptor[4] | Treatment of dementia caused by Alzheimer's disease[30] | |
Nicotine | 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, and is naturally found in tobacco | Agonist of the nicotinic receptor, α4β2[32]
|
Treatment of tobacco dependence[33] | |
Carbachol | Miostat | 2-[(aminocarbonyl)oxy]-N,N,N-trimethylethanaminium | Intraocular solution | Cholinergic agonist[34] | Treatment of glaucoma | |
Suxamethonium chloride (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[35] | Short acting muscle relaxant[36] | |
Epibatidine | Not listed | 2-(6-chloropyridin-3-yl)-7-azabicyclo[2.2.1]heptane | Not listed | Agonist of the nicotinic acetylcholine receptor[37] | Not used as a drug |
Other nicotinic agonists, albeit generally with limited clinical use, include:
- Ganglion type nicotinic receptors and also affects sensory nerve terminals[32]
- α7 receptors[32]
- muscle type receptors, similarly to suxamethonium[32]
Nicotinic versus muscarinic activity
Comparison of cholinergic agonists[38] | ||||
---|---|---|---|---|
Substance | Receptor specificity | Hydrolysis by acetylcholinesterase |
Comments | |
Muscarinic | Nicotinic | |||
Choline | +++ | +++ | ++ | Essential nutrient |
Acetylcholine | +++ | +++ | +++ | Endogenous ligand |
Carbachol | ++ | +++ | - | Used in the treatment of glaucoma |
Methacholine | +++ | + | ++ | |
Bethanechol | +++ | - | - | Used in bladder and gastrointestinal hypotonia. |
Muscarine | +++ | - | - | Natural alkaloid found in certain mushrooms. Cause of mushroom poisoning |
Nicotine | - | +++ | - | Natural alkaloid found in the tobacco plant .
|
Pilocarpine | ++ | - | - | Used in glaucoma |
Oxotremorine | ++ | - | - |
Current status
Currently nicotine receptor agonist research and drug designing is aimed for treatment of multiple diseases and disorders of the CNS.[39]
Targacept has three drug candidates that are in
Memory pharmaceuticals with its partner
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.[42]
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
See also
- Muscarinic acetylcholine receptor
- Muscarinic agonist
- Muscarinic antagonist
- Nicotinic acetylcholine receptor
- Nicotinic antagonist
- Parasympathomimetic drug
References
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External links
Media related to Nicotinic agonists at Wikimedia Commons
- nicotinic+agonists at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- MeSH list of agents 82018722