The common asthma drug salbutamol may offer potential as a treatment for Alzheimer’s disease

0
117

A new study reveals that the common asthma drug salbutamol may offer potential as a treatment for Alzheimer’s disease.

Alzheimer’s disease is the most common form of dementia, affecting 47 million people worldwide and its prevalence is expected to triple to more than 130 million cases by 2050.

No effective treatments that cure the disease or slow down its progression have been discovered. However, this new early-stage study has revealed that repurposing an existing drug, salbutamol, offers significant potential as a low cost and rapid response option.

Extensive analytical in-vitro experiments conducted by the research team show that salbutamol is effective at reducing the accumulation of insoluble fibres of the tau protein – which is found in the brains of people with Alzheimer’s disease.

These microscopic fibres accumulate into neurofibrillary tangles and can cause neuron destabilisation, brain cell death, and are a key characteristic of the disease’s progression.

Much Alzheimer’s disease research has focused on the build-up of amyloid plaques, caused by misfolding of the amyloid-β protein. However, because of disappointing results from numerous therapies targeting Aβ aggregation, more attention is shifting towards tau.

This study, led by researchers at Lancaster University, used a new automated ‘high throughput’ screening approach to study the structure of the misfolding tau protein with a special analytical technique called ‘Synchrotron Radiation Circular Dichroism’ (SRCD) at Diamond Light Source, the UK national synchrotron light source in Oxfordshire.

With this powerful technique they were able to look at a selection of more than 80 existing compounds and drugs simultaneously to determine their effectiveness at preventing the formation of tau fibrils.

This method confirmed the compound epinephrine, more commonly known as adrenaline, was effective at stabilising the tau proteins and preventing the formation of tau tangles.

However, our bodies do not easily absorb epinephrine and it rapidly gets metabolised, so the scientists then looked at a range of readily available compounds with similar chemical structures. This search revealed four current drugs as possible candidates – etamivan, fenoterol, dobutamine and salbutamol.

Etaminvan and fenoterol were found to have little effect on the assembly of tau tangles. Dobutamine, which is used for the rapid treatment of heart attacks and heart failure, was found to have some benefit.

However, because its effects are very short-lived, and because it needs to be administered intravenously, it is not ideal as a basis for treatment of Alzheimer’s disease.

Further tests using a range of analytical techniques all revealed salbutamol could inhibit tau aggregation in vitro. Tests where salbutamol was added to solutions containing tau resulted in drastically reduced density of fibrous tau structures responsible for the tau neurofibrillary tangles.

The researchers believe that salbutamol interacts with an early stage of tau fibril formation, reducing their ability to form an initial nucleus which drives the aggregation process.

Because it is easily ingested, absorbed into the brain, and remains in the body for several hours, salbutamol has attractive properties as a research avenue for potential new treatment for Alzheimer’s.

Dr David Townsend, of Lancaster university and lead author of the research, said: “Our work highlights the potential impact of repurposing drugs for secondary medical uses, by discovering a novel therapeutic strategy that impedes the molecular pathology of Alzheimer’s disease, and which may have otherwise gone unstudied.

“Salbutamol has already undergone extensive human safety reviews, and if follow up research reveals an ability to impede Alzheimer’s disease progression in cellular and animal models, this drug could offer a step forward, whilst drastically reducing the cost and time associated with typical drug development.”

Professor David Middleton, co-author of the research, said: “This work is in the very early stages and we are some way from knowing whether or not salbutamol will be effective at treating Alzheimer’s disease in human patients.

However, our results justify further testing of salbutamol, and similar drugs, in animal models of the disease and eventually, if successful, in clinical trials.”

Dr Rohanah Hussain, of Diamond Light Source, Senior Beamline Scientist and co-author said: “Diamond B23 beamline unique micro-collimated beam has made high throughput CD possible allowing the screening of many compounds through structural activity correlation crucial in drug discovery.”

The researchers say that current asthma inhalers result in only a small amount of salbutamol reaching the brain and so, if further research is successful, a new delivery method would also need to be developed. They add that future research could also focus on other asthma drugs that are chemically similar to salbutamol, but which circulate in the bloodstream for much longer.


Neuronal agonists and antagonists are very useful tools for neuroscience research, which may have important clinical applications for the treatment of several neurological disorders and for the study of the pathogenesis and progression of the diseases that affect the central and/or peripheral nervous systems [1-7].

A neurotransmitter must bind the active site of its corresponding receptor, in order to activate a signaling system that has specific biological functions [8-10]. Neuronal agonist and antagonist molecules are designed to interact with the neurotransmitter receptor to produce opposite effects.

On one hand, neuronal agonists duplicate the biological functions of the native neurotransmitters [11, 12], whereas antagonist compounds compete and inhibit neurotransmitters, by blocking the active site of the cognate receptor [13-15].

This article provides an overview of the various neuronal agonist and antagonist agents that have been discovered and developed for a variety of neurological-based signaling pathways.

Biogenic Amines-based Neurotransmitters

Type of receptorAgonistsAntagonists (receptor blockers)
Alpha 1Chloroethylclonidine
Cirazoline
Metaraminol
Methoxamine
Midodrine
Phenylephrine
Xylometazoline
Acepromazine
Alfuzosin
Doxazosin
Phenoxybenzamine
Phentolamine
Prazosin
Tamsulosin
Terazosin
Trazodone
Alpha 2Agmatine
Amitraz
Brimonidine
Chloroethylclonidine
Clonidine
Detomidine
Dexmedetomidine
Guanfacine
Lofexidine
Medetomidine
Romifidine
Tizanidine
Xylazine
Atipamezole
Idazoxan
Phentolamine
Trazodone
Typical and atypical antipsychotics
Yohimbine
Beta 1Dobutamine
Isoprenaline
Noradrenaline
Atenolol
Bisoprolol
Metoprolol
Propranolol
Nebivolol
Timolol
Vortioxetine
Beta 2Bitolterol mesylate
Formoterol
Isoprenaline
Levalbuterol
Metaproterenol
Ritodrine
Salbutamol (known as Albuterol in the USA)
Salmeterol
Terbutaline
Butoxamine
ICI-118,551
Paroxetine
Propranolol
Timolol
Beta 3Amibegron
L-796568
Mirabegron
Solabegron
SR 59230A
Table 1. List of agonist and antagonists for alpha- and beta-adrenergic receptors.

Biogenic amines, or monoamines, derive from amino acids and are used in the central and/or peripheral nervous systems for the regulation of homeostasis and/or cognition.

Biogenic amines comprise the following five neurotransmitters: norepinephrine (catecholamine; noradrenalin), epinephrine (catecholamine; adrenalin), dopamine (catecholamine), serotonin and histamine. The first three neurotransmitters belong to the subgroup of catecholamines and derive from the amino acid tyrosine (norepinephrine, epinephrine and dopamine). Serotonin derives from the amino acid tryptophan, whereas histamine is produced from the amino acid histidine.

Norepinephrine (noradrenalin) is mainly present in the autonomic nervous system and regulates heart rate, blood pressure and digestion. In the central nervous system, norepinephrine takes part in the control of attention, sleep and wake cycle and feeding behaviors. The cellular receptors for norepinephrine are divided into two classes: alpha- and beta-adrenergic receptors. Alpha-adrenergic receptors are subdivided into alpha1 and alpha2 subtypes, whereas beta-adrenergic subtype receptors are termed beta1, beta2 and beta3.

Epinephrine (adrenalin) is primarily present in the autonomic nervous system. It has similar functions as norepinephrine and both neurotransmitters bind alpha- and beta-adrenergic receptors. However, epinephrine is more commonly utilized as a hormone by the endocrine compartment.

The list of agonists and antagonists for the various alpha- and beta-adrenergic receptors is reported in Table 1.

Dopamine
Dopamine regulates a variety of functions in the central and peripheral nervous systems, through the interaction with five subtypes of dopamine receptors termed D1, D2, D3, D4 and D5 receptors [16]. Deregulations in the dopaminergic signaling pathways have been reported in several neurological illnesses, such as Parkinson’s disease, effects related to alcoholism and psychiatric conditions, such as bipolar disorder, schizophrenia and depression [16].

Antagonist (in alphabetical order)GenerationApplicationD-type receptor(s) targetedBibliographic references
BenperidolFirstTypical antipsychotic (schizophrenia)D2 and some serotonin receptors[1718]
ChlorpromazineFirstTypical antipsychotic (schizophrenia)High binding affinity for D3. Chlorpromazine also binds D1, D2, D4 and D5.[1920]
Clopenthixol (Sordinol)FirstTypical antipsychotic (not approved for use in the U.S.A.)D1 and D2[17]
DroperidolFirstTypical antipsychotic and antiemeticD2[17]
HaloperidolFirstTypical antipsychotic (schizophrenia)High affinity binding for D2, D3 and D4. It also binds with lower affinity D1 and D5.[171920]
FluphenazineFirstTypical antipsychotic (schizophrenia)High affinity for D2 and D3. It also binds with lower affinity D1 and D5.[171920]
FlupenthixolFirstTypical antipsychotic (schizophrenia and antidepressant)D1, D2, D3 and D5[1719]
FluspirileneFirstTypical antipsychotic (schizophrenia)D2[17]
Penfluridol (Semap, Micefal, Longoperidol)FirstTypical antipsychotic (schizophrenia and other similar disorders)D2[17]
PerazineFirstTypical antipsychotic (schizophrenia)D3[1721]
PerphenazineFirstTypical antipsychotic (agitated derpession)D1 and D2[17]
PimozideFirstTypical antipsychotic (schizophrenia and Tourette syndrome)High affinity for D2 and D3. It also binds with lower affinity D4.[1719]
SpiperoneFirstTypical antipsychotic (schizophrenia)High affinity for D2, D3 and D4. It also binds with lower affinity D1.[1719]
SulpirideFirstTypical antipsychotic (schizophrenia and antidepressant)D2 and D3[17]
ThioridazineFirstTypical antipsychotic (schizophrenia)High affinity for D2, D3 and D4. It also binds with lower affinity D1 and D5.[19]
Amisulpride (Solian)SecondAtypical antipsychotics (schizophrenia, depression and bipolar disorder)D2 and D3[19]
Asenapine (Saphris and Sycrest)SecondAtypical antipsychotics (schizophrenia and bipolar disorder)D2, D3 and D4[22]
Aripiprazole (Abilify)SecondAtypical antipsychotics (schizophrenia. bipolar disorder and depression)D2Aripiprazole is a partial antagonist of D3[172223]
Clozapine (Clozaril)SecondAtypical antipsychotics (schizophrenia)D2 and D3[19]
LoxapineSecondAtypical antipsychotics (schizophrenia and bipolar disorder)D2, D3 and D4[24]
NemonaprideSecondAtypical antipsychoticsD3, D4 and D5[20]
Olanzapine (Zyprexa)SecondAtypical antipsychotics (schizophrenia and bipolar disorder)D1, D2, D3, D4 and D5[19]
Quetiapine (Seroquel)SecondAtypical antipsychotics (schizophrenia, bipolar disorder and major depression)D1, D2 and D4. It also binds with lower affinity D4[19]
Paliperidone (Invega)SecondAtypical antipsychotics (schizophrenia and schizoaffective disorders)D2, D3 and D4. It also binds with lower affinity D1 and D5.[25]
Remoxipride (Roxiam)SecondAtypical antipsychotics (schizophrenia).Moderate binding affinity for D2[171926]
Risperidone (Risperdal)SecondAtypical antipsychotics (schizophrenia and bipolar disorder).D2, D3 and D4[171925]
TiaprideSecondAtypical antipsychotics (alcohol dependence, dyskinesia, Huntington’s chorea and psychomotor agitations).D2 and D3[1727]
Ziprasidone (Geodon)SecondAtypical antipsychotics (schizophrenia, bipolar disorders and depression).D2[1728]
Domperidone (Motilium)Nausea and vomiting (antiemetic, gastroprokinetic agent and galactagogue).D2[2930]
BromoprideNausea and vomiting (antiemetic).D2 and D3[1731]
MetoclopramideNausea and vomiting (utilized for the treatment of gastroparesis).D2[1732]
EticlopridePharmacological research.D2 and D3[192033]
NafadotridePharmacological research.D2 and D3[171920]
RaclopridePharmacological research.D2 and D3[1719]
Table 2. List of D-type dopamine receptors that are blocked by various dopamine antagonists.

The modulation of dopamine activity either by agonists or antagonists may allow for a better understanding of signaling pathways that are associated with the biological effects of dopamine and, possibly, lead to the discovery and/or development of novel therapeutics for the treatment of the aforementioned neurological diseases [16].

There are two subclasses of dopamine agonists: ergoline and non-ergoline dopamine agonists [34], which interact with the type D2 dopamine receptor. Ergoline dopamine agonists comprise: lisuride, bromocriptine, cabergoline and bromocriptine [35-39], whereas non-ergoline dopamine agonists include pramipexole and ropinirole [34, 40].

Apomorphine was among the first dopamine agonists to be developed and interacts with type D1 and type D2 dopamine receptors [41-43].

To date, two generations of dopamine antagonists have been developed and utilized as antipsychotics [44-47], other dopamine antagonists are used for the treatment of nausea and vomiting, whereas some dopamine antagonists are only utilized for investigational purposes. Dopamine antagonists have been designed to block the entire range of D-type dopamine receptors (see Table 2).

The investigational dopamine antagonists comprise: eticlopride [19, 33], nafadotride [19] and raclopride [19]. Interestingly, raclopride can also be utilized in PET imaging to monitor the clinical course in patients with Huntington’s disease [48].

Type Serotonin receptor agonists Functions
5-HT1A Aripiprazole Partial agonist. Atypical antipsychotic, schizophrenia
Asenapine Partial agonist. Atypical antipsychotic, schizophrenia
Azapirones (buspirone, gepirone and tandospirone) Partial agonists. Antidepressants, anxiolytics
Clozapine Partial agonist. Atypical antipsychotic, schizophrenia
Flibanserin Partial agonist. Sexual dysfunctions in women
Lurasidone Partial agonist. Atypical antipsychotic, schizophrenia
Quetiapine Partial agonist. Atypical antipsychotic, schizophrenia
Vilazodone Partial agonist. Antidepressant
Vortioxetine Partial agonist. Antidepressant
Ziprasidone Partial agonist. Atypical antipsychotic, schizophrenia
5-HT1B Eltoprazine Under development for the control of aggressive behavior
Ergotamine Antimigraine
Serenics (batoprazine, eltoprazine and fluprazine) Reduce aggressive behavior in animal models
Tryptans (naratriptan, rizatriptan and sumatriptan) Used for the treatment of migraine and cluster headache attacks
5-HT1D Ergotamine
Tryptans. Antimigraine
5-HT1E Eletriptan (tryptan) Antimigraine
BRL-54443 Used in research
5-HT1F BRL-54443 Used in research
Lasmiditan Under development for the treatment of migraine
Tryptans (eletriptan, naratriptan and sumatriptan) Antimigraine
5-HT2A 25-NB series Phenethylamine serotonergic psychedelic. Highly selective for 5-HT2A 5-HT2A receptor may cause hallucination, agitation, aggression, hypertension, tachycardia, hyperthermia, hyperpyrexia. clonus and seizures.
LSD Serotonergic psychedelic, hallucinogenic effect
Mescaline Serotonergic psychedelic, hallucinogenic effect
Psilocybin Serotonergic psychedelic, hallucinogenic effect
5-HT2B LSD Serotonergic psychedelic, hallucinogenic effect
Psilocybin Serotonergic psychedelic, hallucinogenic effect
Cabergoline Cardiac fibrosis
Fenfluramine Cardiac fibrosis
Pergolide Cardiac fibrosis
5-HT2C meta-Chlorophenylpiperazine (mCPP) Anxiety, depression and panic attacks
Lorcaserin Anti-obesity drug, appetite suppressant
5-HT3 2-Methyl-5-hydroxytryptamine (2-methylserotonin)
Quipazine Used in research
5-HT4 Cisapride
Prucalopride
Tegaserod Gastrointestinal motility
5-HT5A Valerenic acid Facilitate sleep
5-HT6 E-6801
E-6837
EMDT
WAY-181
WAY-187
WAY-208
WAY-466 These specific 5-HT6 receptor agonists have not been approved for therapeutic applications. Studies in animal models showed negative effects on cognition and memory.
5-HT7 AS-19 Used in research
non-selective Serotonergic psychedelics (amphetamines, lysergamindes, phenethylamines and tryptamines) The hallucinogenic effects of serotonergic psychedelics derive from the stimulation of the 5-HT2A receptor.
Table 4. List of serotonin receptors agonists.
Serotonin
Serotonin derives from the amino acid tryptophan. The majority of serotonin-secreting neurons are situated in the brainstem and their axons are projected into several areas of the brain. The functions of serotonin comprise feeding behaviors, daily rhythms, and regulation of mood, emotions and attention. The binding of serotonin to its cognate receptors regulate the secretion of several neurotransmitters and hormones. The neurotransmitters that are released following the stimulation of the serotonin-dependent axis comprise dopamine, epinephrine and/or norepinephrine, acetylcholine, glutamate and gamma-aminobutyric acid (GABA), whereas the hormones that are serotonin-dependent include prolactin, oxytocin, cortisol, substance P, corticotropin, vasopressin, along with several other kinds of hormones.

Type Serotonin receptor antagonists Functions
5-HT1A
Quetiapine (seroquel) Atypical antipsychotic. Quetiapine also inhibits dopamine receptors D1 and D2, histamine receptor H1, and A1 adrenoreceptors.
Methysergide Atypical antipsychotic. Methysergide is a nonselective 5-HT1 receptor blocker. It may cause retroperitoneal fibrosis and mediastinal fibrosis.
5-HT2A Clozapine Atypical antipsychotic. Clozapine also inhibits D4 receptor.
Cyproheptadine (periactin) Atypical antipsychotic. Cyproheptadine also inhibits histamine receptor H1.
Ketanerin Antihypertensive. Ketanerin also inhibits alpha 1 adrenoreceptor.
Methysergide Atypical antipsychotic. It may cause retroperitoneal fibrosis and mediastinal fibrosis.
Nefazodone Antidepressant
Risperidone (risperdal) Atypical antipsychotic
Quetiapine (seroquel) Atypical antipsychotic. Quetiapine also inhibits dopamine receptors D1 and D2, histamine receptor H1, and A1 adrenoreceptors.
Trazodone Antidepressant
5-HT2C
Clozapine
Ketanerin Atypical antipsychotic. Clozapine also inhibits D4 receptor. Antihypertensive. Ketanerin also inhibits alpha 1 adrenoreceptors.
5-HT3
Dolasetron
Granisetron
Ondansetron
Palonosetron
Tropisetron Treatment for chemotherapy-associated emesis. Postoperative nausea and vomiting
Alosetron
Cilansetron Irritable bowel syndrome
Mirtazapine Antidepressant
Non-selective
Chlorpromazine
Cyproheptadine
Metergoline
Methysergide
Mianserin
Mirtazapine
Oxetorone
Pizotifen
Propranolol
Ritanserin
Spiperone This list includes some of the non-selective HT antagonists.
Other types of serotonin inhibitors Fenclonine (para-chlorophenylalanine) Inhibits the enzyme tryptophan hydroxylase, which is required for the biosynthesis of serotonin. It is used for the treatment of carcinoid syndrome.
Reserpine Reduces serotonin levels in the brain, heart and other organs. It is used for the treatment of hypertension and depression.
Table 5. List of serotonin receptor antagonists.
The serotonin receptors are also termed 5-hydroxytryptamine receptors (5-HT receptors) and are situated in the central and peripheral nervous systems [49]. The serotonin receptors have been classified into 7 families of G protein-coupled receptors, with the exception of a ligand-gated ion channel receptor termed 5-HT3 (Table 3). In addition, there are some subtypes of serotonin receptors (Table 3) [50].

Many pharmaceutical and recreational drugs interact with serotonin receptors, such as antipsychotics, antidepressants, antiemetics, hallucinogens, anorectics, antiemetics antimigraine compounds, entactogens and gastroprokinetic agents [51].

The list of serotonin receptor agonists is reported in Table 4, whereas the list of serotonin receptor antagonists is shown in Table 5.

Histamine
Histamine is synthesized from the amino acid histidine. There are four histamine receptors, termed H1, H2, H3 and H4.

Compound Histamine receptor/receptors targeted Type of action Biological functions
Histamine dihydrochloride All histamine receptors Endogenous histamine receptor agonist. Inflammatory responses, physiological activities of the intestine, neurotransmitter and has vasodilatory and bronchoconstriction properties.
Histamine phosphate All histamine receptors Agonist Functions as neurotransmitter in the nervous system. It can also act as a local mediator in the intestine, skin, and immune system.
Histamine trifluoromethyl toluidide (HTMT) dimaleate H1 and H2 receptors Agonist. Stimulates the inositol triphosphate (IP3) and calcium signaling pathway and promotes the proliferation of small cholangiocytes. It is also active in vivo.
A 943931 dihydrochloride H4 receptor Antagonist Anti-inflammatory and analgesic effects in vivo.
Asenapine maleate Histamine receptors Antagonist. It can also inhibit 5-HT receptors, dopamine receptor and adrenoceptors. Antipsychotic.
Astermizole H1 receptor Antagonist. It can also inhibit the hERG K+ channel. It is a strong selective inhibitor of H1 receptor. It is also a potent inhibitor of the hERG K+ channel. It is active in vivo and in vitro.
Bepotastine besilate H1 receptor Antagonist Reduces mast cell activity. It also inhibits eosinophilic infiltration, IL-5 production, leukotriene B4 (LTB4) and leukotriene D4 (LTD4) activity.
Betahistine dihydrochloride H1 receptor H1 receptor agonist and H3 receptor antagonist. Enhances cochlear blood flow in the in vivo system.
Cimetidine sulfoxide H2 receptor Antagonist Takes part in the paracellular cimetidine absorption in the jejunum.
Ebastine H1 receptor Antagonist It is a substrate of the oxygenase cytochrome P450 2J2 (CYP2J2), which takes part in the regulation of the metabolism of drugs.
Epinastine hydrochloride H1 receptor Antagonist Reduces the activities of mast cells.
Fexofenadine hydrochloride (MDL 16,455A Terfenidine) H1 receptor Antagonist Antiallergenic
JNJ-7777120 H4 receptor Antagonist It is a highly selective potent inhibitor of the H4 receptor. It exhibits anti-inflammatory, antifibrotic and antiallergic properties in the in vivo system.
Loratidine (Loratadine, SCH 29851) H1 receptor Antagonist Antiallergenic.
Olanzapine Histamine receptors Antagonist. It can also block 5-HT, muscarinic receptor and dopamine receptor. Atypical antipsychotic. It also shows anxiolytic activity.
Olopatadine hydrochloride H1 receptor Antagonist Reduces the release of histamine.
Pheniramine maleate H1 receptor Antagonist Antihistaminic and anticholinergic properties. It is utilized for the treatment of allergic conditions, including hay fever and urticaria.
Roxatidine acetate hydrochloride H2 receptor Antagonist Decreases VEGF expression levels, inhibits platelet function and gastric acid secretion.
VUF8430 dihydrobromide H4 receptor Antagonist It can be used in neuroscience and for the study of neurotransmission.
Table 6. List of histamine receptor agonists and antagonists.
The expression of H1 receptors in the central nervous system is involved in the regulation of attention and arousal. The stimulation of H1 receptors in other parts of the body may cause skin rashes, vasodilation originated by smooth muscle relaxation, disconnection of blood vessels cell-lining and bronchoconstriction. H1 receptor overactivation is related to the symptoms of seasonal allergies.

H2 receptors are expressed in the parietal cells that are situated in the lining of the stomach and regulate the levels of gastric acid. H2 receptors are also expressed in the uterus, vascular smooth muscle cells, heart and neutrophils.

H3 receptors are situated in the entire nervous system and control the levels of histamine in the body, in order to avoid an overexpression. Thus, the binding of histamine to H3 receptors stimulates signals that reduce the production of histamine.

FamilySubtypesReceptor classification
5-HT15-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
Gi/Go-protein coupled
5-HT25-HT2A
5-HT2B
5-HT2C
GqG11-protein coupled
5-HT3Ligand-gated Na+ and K+ cation channel
5-HT4Gs-protein coupled
5-HT55-HT5A
5-HT5B
Gi/Go-protein coupled
5-HT6Gs-protein coupled
5-HT7Gs-protein coupled
Table 3. List of serotonin receptors.

H4 receptors regulate the release of white blood cells from the bone marrow. H4 receptors are expressed in the bone marrow, basophils, thymus, spleen and small intestine.

The list of histamine receptor agonists and antagonists is reported in Table 6.

Serotonin-dependent neurotransmitters. As anticipated, serotonin-related axis may stimulate the expression of acetylcholine (ACh), glutamate and gamma-aminobutyric acid (GABA), along with the already described biogenic amines: dopamine, epinephrine and/or norepinephrine.

Acetylcholine
Choline acetyltransferase carries out the acetylation of choline, in order to synthetize acetylcholine (ACh). There are two main classes of acetylcholine receptors (AChR): nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). Nicotinic acetylcholine receptors are stimulated by nicotine and are expressed in postganglionic neurons in the sympathetic ganglia and in the adrenal medulla, whereas muscarinic are present on sweat glands of the skin.

Nicotinic acetylcholine receptors agonists include: nicotine, choline, cytisine, epibatidine, lobeline and varenicline. Nicotinic acetylcholine receptors antagonists comprise the following four groups:

Ganglionic blocking agents (hexamethonium, mecamylamine and trimethaphan).
Nondepolarizing neuromuscular blocking agents (atracurium, doxacurium, mivacurium, pancuronium, tubocurarine and vecuronium).
Depolarizing neuromuscular blocking agent succinylcholine.
Centrally acting nicotinic antagonists (18-methoxycoronaridine, 3-methoxymorphinan, dextromethorphan and dextrorphan).
Muscarinic acetylcholine receptors agonists comprise: bethanechol, cevimeline, homatropine, homatropine methylbromide, methacholine, NGX267, pilocarpine and xanomeline.

The list of muscarinic acetylcholine receptors antagonists include the following compounds: atropine (D/L-hyoscyamine), atropine methonitrate, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, ipratropium, mebeverine, oxybutynin, pirenzepine, procyclidine, scopolamine (L-hyoscine), solifenacin, tropicamide, tiotropium, trihexyphenidyl (benzhexol)and tolterodine.

Glutamate
Glutamate receptors are mainly expressed on the membrane of neuronal and glial cells [52] and they can be either synaptic or non-synaptic receptors for glutamate.

Glutamate receptors agonists include: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), glutamic acid, ibotenic acid, kainic acid, N-Methyl-D-aspartic acid and quisqualic acid.

The list of glutamate receptors antagonists comprise the subsequent drugs: (2R)-amino-5-phosphonovaleric acid (AP5), barbiturates, dextromethorphan, dextrorphan, dizocilpine, ibogaine, ifenprodil, ketamine, kynurenic acid, memantine, nitrous oxide, perampanel and phencyclidine.

Gamma-aminobutyric Acid (GABA)
GABA receptors are expressed in the mature central nervous system of vertebrates and comprise two classes: GABAA and GABAB receptors.

GABAA receptors are also termed inotropic receptors and consist of ligand-gated ion channels, whereas GABAB receptors are also known as metabotropic receptors and are G protein-coupled receptors.

GABAA receptors agonists include: bamaluzole, gabamide, γ-Amino-β-hydroxybutyric acid (GABOB), gaboxadol, gaboxadol, ibotenic acid, isoguvacine, isonipecotic acid, muscimol, phenibut, picamilon, progabide, progabide acid (SL- 75102), propofol, quisqualamine, thiomuscimol, topiramate and zolpidem. In addition, there are positive allosteric modulator (PAM) molecules that enhance the GABAA receptors activity through allosteric modulation, which does not involve the binding the GABA active site on the receptor. The list of GABAA receptors positive allosteric modulators comprise the following compounds: alcohols (ethanol, isopropanol), allopregnanolone, avermenctins, barbiturates, benzodiazepines, nonbenzodiazepines, bromides, carbamates, chloralose, chlormezanone, clomethiazole, dihydroergolines, disulfonylalkanes, etazepine, etifoxine, imidazoles, kavalactones, loreclezole, petrichloral, propofol, piperidinediones, propanidid, pyrazolopyridines, quinazolinones, stiripentol, valeric acid, valerenic acid and volatile organic compounds, such as chloral hydrate, chloroform, diethyl ether and sevoflurane.

GABAA receptors antagonists include: bicuculline, ciprofloxacin, flumazenil, metrazol and thujone. Negative allosteric modulators for GABAA receptors comprise the following compounds: basmisanil, flumazenil, L-655,708, MRK-016, PWZ-029, Ro4938581, and TB-21007.

GABAB receptors agonists include: 1,4-butanediol, baclofen, gabamide, GABOB, gamma-butyrolactone, gamma-hydroxybutyric acid, gamma-hydroxyvaleric acid, gamma-valerolacone, lesogaberan, phenibut, picamilon, progabide, SL-75102 and tolgabide. The drug ADX71441 is a positive allosteric modulator for GABAB receptors [53].

GABAB receptors antagonists comprise the following drugs: 2-OH-saclofen, 2-phenethylamine, CGP-35348, CGP-52432, CGP-55845, ginsenosides [54], homotaurine [55], phaclofen, SCH-50911 and SGS-742 [56].

TypeSerotonin receptor agonistsFunctions
5-HT1AAripiprazolePartial agonist. Atypical antipsychotic, schizophrenia
AsenapinePartial agonist. Atypical antipsychotic, schizophrenia
Azapirones (buspirone, gepirone and tandospirone)Partial agonists. Antidepressants, anxiolytics
ClozapinePartial agonist. Atypical antipsychotic, schizophrenia
FlibanserinPartial agonist. Sexual dysfunctions in women
LurasidonePartial agonist. Atypical antipsychotic, schizophrenia
QuetiapinePartial agonist. Atypical antipsychotic, schizophrenia
VilazodonePartial agonist. Antidepressant
VortioxetinePartial agonist. Antidepressant
ZiprasidonePartial agonist. Atypical antipsychotic, schizophrenia
5-HT1BEltoprazineUnder development for the control of aggressive behavior
ErgotamineAntimigraine
Serenics (batoprazine, eltoprazine and fluprazine)Reduce aggressive behavior in animal models
Tryptans (naratriptan, rizatriptan and sumatriptan)Used for the treatment of migraine and cluster headache attacks
5-HT1DErgotamine
Tryptans.
Antimigraine
5-HT1EEletriptan (tryptan)Antimigraine
BRL-54443Used in research
5-HT1FBRL-54443Used in research
LasmiditanUnder development for the treatment of migraine
Tryptans (eletriptan, naratriptan and sumatriptan)Antimigraine
5-HT2A25-NB seriesPhenethylamine serotonergic psychedelic. Highly selective for 5-HT2A 5-HT2A receptor may cause hallucination, agitation, aggression, hypertension, tachycardia, hyperthermia, hyperpyrexia. clonus and seizures.
LSDSerotonergic psychedelic, hallucinogenic effect
MescalineSerotonergic psychedelic, hallucinogenic effect
PsilocybinSerotonergic psychedelic, hallucinogenic effect
5-HT2BLSDSerotonergic psychedelic, hallucinogenic effect
PsilocybinSerotonergic psychedelic, hallucinogenic effect
CabergolineCardiac fibrosis
FenfluramineCardiac fibrosis
PergolideCardiac fibrosis
5-HT2Cmeta-Chlorophenylpiperazine (mCPP)Anxiety, depression and panic attacks
LorcaserinAnti-obesity drug, appetite suppressant
5-HT32-Methyl-5-hydroxytryptamine (2-methylserotonin)
Quipazine
Used in research
5-HT4Cisapride
Prucalopride
Tegaserod
Gastrointestinal motility
5-HT5AValerenic acidFacilitate sleep
5-HT6E-6801
E-6837
EMDT
WAY-181
WAY-187
WAY-208
WAY-466
These specific 5-HT6 receptor agonists have not been approved for therapeutic applications. Studies in animal models showed negative effects on cognition and memory.
5-HT7AS-19Used in research
non-selectiveSerotonergic psychedelics (amphetamines, lysergamindes, phenethylamines and tryptamines)The hallucinogenic effects of serotonergic psychedelics derive from the stimulation of the 5-HT2A receptor.
Table 4. List of serotonin receptors agonists.
TypeSerotonin receptor antagonistsFunctions
5-HT1A
Quetiapine (seroquel)
Atypical antipsychotic. Quetiapine also inhibits dopamine receptors D1 and D2, histamine receptor H1, and A1 adrenoreceptors.
MethysergideAtypical antipsychotic. Methysergide is a nonselective 5-HT1 receptor blocker. It may cause retroperitoneal fibrosis and mediastinal fibrosis.
5-HT2AClozapineAtypical antipsychotic. Clozapine also inhibits D4 receptor.
Cyproheptadine (periactin)Atypical antipsychotic. Cyproheptadine also inhibits histamine receptor H1.
KetanerinAntihypertensive. Ketanerin also inhibits alpha 1 adrenoreceptor.
MethysergideAtypical antipsychotic. It may cause retroperitoneal fibrosis and mediastinal fibrosis.
NefazodoneAntidepressant
Risperidone (risperdal)Atypical antipsychotic
Quetiapine (seroquel)Atypical antipsychotic. Quetiapine also inhibits dopamine receptors D1 and D2, histamine receptor H1, and A1 adrenoreceptors.
TrazodoneAntidepressant
5-HT2C
Clozapine
Ketanerin
Atypical antipsychotic. Clozapine also inhibits D4 receptor. Antihypertensive. Ketanerin also inhibits alpha 1 adrenoreceptors.
5-HT3
Dolasetron
Granisetron
Ondansetron
Palonosetron
Tropisetron
Treatment for chemotherapy-associated emesis. Postoperative nausea and vomiting
Alosetron
Cilansetron
Irritable bowel syndrome
MirtazapineAntidepressant
Non-selective
Chlorpromazine
Cyproheptadine
Metergoline
Methysergide
Mianserin
Mirtazapine
Oxetorone
Pizotifen
Propranolol
Ritanserin
Spiperone
This list includes some of the non-selective HT antagonists.
Other types of serotonin inhibitorsFenclonine (para-chlorophenylalanine)Inhibits the enzyme tryptophan hydroxylase, which is required for the biosynthesis of serotonin. It is used for the treatment of carcinoid syndrome.
ReserpineReduces serotonin levels in the brain, heart and other organs. It is used for the treatment of hypertension and depression.
Table 5. List of serotonin receptor antagonists.
CompoundHistamine receptor/receptors targetedType of actionBiological functions
Histamine dihydrochlorideAll histamine receptorsEndogenous histamine receptor agonist.Inflammatory responses, physiological activities of the intestine, neurotransmitter and has vasodilatory and bronchoconstriction properties.
Histamine phosphateAll histamine receptorsAgonistFunctions as neurotransmitter in the nervous system. It can also act as a local mediator in the intestine, skin, and immune system.
Histamine trifluoromethyl toluidide (HTMT) dimaleateH1 and H2 receptorsAgonist.Stimulates the inositol triphosphate (IP3) and calcium signaling pathway and promotes the proliferation of small cholangiocytes. It is also active in vivo.
A 943931 dihydrochlorideH4 receptorAntagonistAnti-inflammatory and analgesic effects in vivo.
Asenapine maleateHistamine receptorsAntagonist. It can also inhibit 5-HT receptors, dopamine receptor and adrenoceptors.Antipsychotic.
AstermizoleH1 receptorAntagonist. It can also inhibit the hERG K+ channel.It is a strong selective inhibitor of H1 receptor. It is also a potent inhibitor of the hERG K+ channel. It is active in vivo and in vitro.
Bepotastine besilateH1 receptorAntagonistReduces mast cell activity. It also inhibits eosinophilic infiltration, IL-5 production, leukotriene B4 (LTB4) and leukotriene D4 (LTD4) activity.
Betahistine dihydrochlorideH1 receptorH1 receptor agonist and H3 receptor antagonist.Enhances cochlear blood flow in the in vivo system.
Cimetidine sulfoxideH2 receptorAntagonistTakes part in the paracellular cimetidine absorption in the jejunum.
EbastineH1 receptorAntagonistIt is a substrate of the oxygenase cytochrome P450 2J2 (CYP2J2), which takes part in the regulation of the metabolism of drugs.
Epinastine hydrochlorideH1 receptorAntagonistReduces the activities of mast cells.
Fexofenadine hydrochloride (MDL 16,455A Terfenidine)H1 receptorAntagonistAntiallergenic
JNJ-7777120H4 receptorAntagonistIt is a highly selective potent inhibitor of the H4 receptor. It exhibits anti-inflammatory, antifibrotic and antiallergic properties in the in vivo system.  
Loratidine (Loratadine, SCH 29851)H1 receptorAntagonistAntiallergenic.
OlanzapineHistamine receptorsAntagonist. It can also block 5-HT, muscarinic receptor and dopamine receptor.Atypical antipsychotic. It also shows anxiolytic activity.
Olopatadine hydrochlorideH1 receptorAntagonistReduces the release of histamine.
Pheniramine maleateH1 receptorAntagonistAntihistaminic and anticholinergic properties. It is utilized for the treatment of allergic conditions, including hay fever and urticaria.
Roxatidine acetate hydrochlorideH2 receptorAntagonistDecreases VEGF expression levels, inhibits platelet function and gastric acid secretion.
VUF8430 dihydrobromideH4 receptorAntagonistIt can be used in neuroscience and for the study of neurotransmission.
Table 6. List of histamine receptor agonists and antagonists

References

  1. Margolis E, Karkhanis A. Dopaminergic cellular and circuit contributions to kappa opioid receptor mediated aversion. Neurochem Int. 2019;129:104504 pubmed publisher
  2. Mufson E, Counts S, Ginsberg S, Mahady L, Perez S, Massa S, et al. Nerve Growth Factor Pathobiology During the Progression of Alzheimer’s Disease. Front Neurosci. 2019;13:533 pubmed publisher
  3. Barbullushi K, Abati E, Rizzo F, Bresolin N, Comi G, Corti S. Disease Modeling and Therapeutic Strategies in CMT2A: State of the Art. Mol Neurobiol. 2019;: pubmed publisher
  4. Zheng Y, Smith P. Cannabinoid drugs: will they relieve or exacerbate tinnitus?. Curr Opin Neurol. 2019;32:131-136 pubmed publisher
  5. Nepovimova E, Janockova J, Misik J, Kubik S, Stuchlik A, Vales K, et al. Orexin supplementation in narcolepsy treatment: A review. Med Res Rev. 2019;39:961-975 pubmed publisher
  6. Abraham N, Lewis R. Neuronal Nicotinic Acetylcholine Receptor Modulators from Cone Snails. Mar Drugs. 2018;16: pubmed publisher
  7. Verma M, Goel R, Krishnadas N, Nemmani K. Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders. Expert Opin Ther Targets. 2018;22:615-628 pubmed publisher
  8. Venter J, di Porzio U, Robinson D, Shreeve S, Lai J, Kerlavage A, et al. Evolution of neurotransmitter receptor systems. Prog Neurobiol. 1988;30:105-69 pubmed
  9. Nicoll R, Malenka R, Kauer J. Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system. Physiol Rev. 1990;70:513-65 pubmed
  10. Ferre S, Ciruela F, Woods A, Lluis C, Franco R. Functional relevance of neurotransmitter receptor heteromers in the central nervous system. Trends Neurosci. 2007;30:440-6 pubmed
  11. Hruby V. Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov. 2002;1:847-58 pubmed
  12. Hilditch A, Drew G. Effects of dopamine receptor agonists and antagonists at peripheral neuronal and vascular dopamine receptors in the anaesthetised dog. J Cardiovasc Pharmacol. 1984;6:460-9 pubmed
  13. Kumamoto T, Nakajima M, Uga R, Ihayazaka N, Kashihara H, Katakawa K, et al. Design, synthesis, and evaluation of polyamine-memantine hybrids as NMDA channel blockers. Bioorg Med Chem. 2018;26:603-608 pubmed publisher
  14. Shaw C, Bains J. Synergistic versus antagonistic actions of glutamate and glutathione: the role of excitotoxicity and oxidative stress in neuronal disease. Cell Mol Biol (Noisy-le-grand). 2002;48:127-36 pubmed
  15. Wang D, Hu M, Li X, Zhang D, Chen C, Fu J, et al. Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem. 2019;168:207-220 pubmed publisher
  16. Beaulieu J, Espinoza S, Gainetdinov R. Dopamine receptors – IUPHAR Review 13. Br J Pharmacol. 2015;172:1-23 pubmed
  17. Beaulieu J, Gainetdinov R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182-217 pubmed publisher
  18. Leucht S, Hartung B. Benperidol for schizophrenia. Cochrane Database Syst Rev. 2005;:CD003083 pubmed
  19. Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, et al. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets. 2006;5:25-43 pubmed
  20. Missale C, Nash S, Robinson S, Jaber M, Caron M. Dopamine receptors: from structure to function. Physiol Rev. 1998;78:189-225 pubmed
  21. Heidbreder C, Newman A. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann N Y Acad Sci. 2010;1187:4-34 pubmed publisher
  22. Stoner S, Pace H. Asenapine: a clinical review of a second-generation antipsychotic. Clin Ther. 2012;34:1023-40 pubmed publisher
  23. Brown R, Taylor M, Geddes J. Aripiprazole alone or in combination for acute mania. Cochrane Database Syst Rev. 2013;:CD005000 pubmed publisher
  24. Popovic D, Nuss P, Vieta E. Revisiting loxapine: a systematic review. Ann Gen Psychiatry. 2015;14:15 pubmed publisher
  25. Corena McLeod M. Comparative Pharmacology of Risperidone and Paliperidone. Drugs R D. 2015;15:163-74 pubmed publisher
  26. Nadal R. Pharmacology of the atypical antipsychotic remoxipride, a dopamine D2 receptor antagonist. CNS Drug Rev. 2001;7:265-82 pubmed
  27. Dose M, Lange H. The benzamide tiapride: treatment of extrapyramidal motor and other clinical syndromes. Pharmacopsychiatry. 2000;33:19-27 pubmed
  28. Stahl S, Shayegan D. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry. 2003;64 Suppl 19:6-12 pubmed
  29. Reddymasu S, Soykan I, McCallum R. Domperidone: review of pharmacology and clinical applications in gastroenterology. Am J Gastroenterol. 2007;102:2036-45 pubmed
  30. Barone J. Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother. 1999;33:429-40 pubmed
  31. Tonini M, Cipollina L, Poluzzi E, Crema F, Corazza G, De Ponti F. Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther. 2004;19:379-90 pubmed
  32. Matsui A, Matsuo H, Takanaga H, Sasaki S, Maeda M, Sawada Y. Prediction of catalepsies induced by amiodarone, aprindine and procaine: similarity in conformation of diethylaminoethyl side chain. J Pharmacol Exp Ther. 1998;287:725-32 pubmed
  33. Martelle J, Nader M. A review of the discovery, pharmacological characterization, and behavioral effects of the dopamine D2-like receptor antagonist eticlopride. CNS Neurosci Ther. 2008;14:248-62 pubmed publisher
  34. Brooks D. Dopamine agonists: their role in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2000;68:685-9 pubmed
  35. Auriemma R, Pirchio R, De Alcubierre D, Pivonello R, Colao A. Dopamine Agonists: From the 1970s to Today. Neuroendocrinology. 2019;109:34-41 pubmed publisher
  36. Hofmann C, Penner U, Dorow R, Pertz H, Jähnichen S, Horowski R, et al. Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis. Clin Neuropharmacol. 2006;29:80-6 pubmed
  37. . DA agonists — ergot derivatives: bromocriptine: management of Parkinson’s disease. Mov Disord. 2002;17 Suppl 4:S53-67 pubmed
  38. Markham A, Benfield P. Pergolide : A Review of its Pharmacology and Therapeutic Use in Parkinson’s Disease. CNS Drugs. 1997;7:328-40 pubmed publisher
  39. Rabey J. Second generation of dopamine agonists: pros and cons. J Neural Transm Suppl. 1995;45:213-24 pubmed
  40. Zhao H, Ning Y, Cooper J, Refoios Camejo R, Ni X, Yi B, et al. Indirect Comparison of Ropinirole and Pramipexole as Levodopa Adjunctive Therapy in Advanced Parkinson’s Disease: A Systematic Review and Network Meta-Analysis. Adv Ther. 2019;36:1252-1265 pubmed publisher
  41. Schwab R, AMADOR L, Lettvin J. Apomorphine in Parkinson’s disease. Trans Am Neurol Assoc. 1951;56:251-3 pubmed
  42. Maggio R, Barbier P, Corsini G. Apomorphine continuous stimulation in Parkinson’s disease: receptor desensitization as a possible mechanism of reduced motor response. J Neural Transm Suppl. 1995;45:133-6 pubmed
  43. Lees A, Stern G. Sustained low-dose levodopa therapy in Parkinson’s disease: a 3-year follow-up. Adv Neurol. 1983;37:9-15 pubmed
  44. Wang S, Han C, Lee S, Jun T, Patkar A, Masand P, et al. Investigational dopamine antagonists for the treatment of schizophrenia. Expert Opin Investig Drugs. 2017;26:687-698 pubmed publisher
  45. Felsing D, Jain M, Allen J. Advances in Dopamine D1 Receptor Ligands for Neurotherapeutics. Curr Top Med Chem. 2019;19:1365-1380 pubmed publisher
  46. Hellings J, Arnold L, Han J. Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline. Expert Opin Pharmacother. 2017;18:581-588 pubmed publisher
  47. Tack J, Masuy I, Van Den Houte K, Wauters L, Schol J, Vanuytsel T, et al. Drugs under development for the treatment of functional dyspepsia and related disorders. Expert Opin Investig Drugs. 2019;28:871-889 pubmed publisher
  48. Pagano G, Niccolini F, Politis M. Current status of PET imaging in Huntington’s disease. Eur J Nucl Med Mol Imaging. 2016;43:1171-82 pubmed publisher
  49. Hoyer D, Clarke D, Fozard J, Hartig P, Martin G, Mylecharane E, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994;46:157-203 pubmed
  50. Wesołowska A. In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. Pol J Pharmacol. 2002;54:327-41 pubmed
  51. Nichols D, Nichols C. Serotonin receptors. Chem Rev. 2008;108:1614-41 pubmed publisher
  52. Brassai A, Suvanjeiev R, Bán E, Lakatos M. Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity. Brain Res Bull. 2015;112:1-6 pubmed publisher
  53. Kannampalli P, Poli S, Boléa C, Sengupta J. Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABAB receptor in a rat model of bladder pain. Neuropharmacology. 2017;126:1-11 pubmed publisher
  54. Kimura T, Saunders P, Kim H, Rheu H, Oh K, Ho I. Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors. Gen Pharmacol. 1994;25:193-9 pubmed
  55. Giotti A, Luzzi S, Spagnesi S, Zilletti L. Homotaurine: a GABAB antagonist in guinea-pig ileum. Br J Pharmacol. 1983;79:855-62 pubmed
  56. Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, et al. SGS742: the first GABA(B) receptor antagonist in clinical trials. Biochem Pharmacol. 2004;68:1479-87 pubmed

Source:
Lancaster University

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.