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, 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 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 [20]. 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 [20].

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 [20].

There are two subclasses of dopamine agonists: ergoline and non-ergoline dopamine agonists [39], which interact with the type D2 dopamine receptor. Ergoline dopamine agonists comprise: lisuride, bromocriptine, cabergoline and bromocriptine [40-44], whereas non-ergoline dopamine agonists include pramipexole and ropinirole [39, 45].

Apomorphine was among the first dopamine agonists to be developed and interacts with type D1 and type D2 dopamine receptors [46-48].

To date, two generations of dopamine antagonists have been developed and utilized as antipsychotics [49-52], 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 [23, 37], nafadotride [23] and raclopride [23]. Interestingly, raclopride can also be utilized in PET imaging to monitor the clinical course in patients with Huntington's disease [53].

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.

The serotonin receptors are also termed 5-hydroxytryptamine receptors (5-HT receptors) and are situated in the central and peripheral nervous systems [54]. 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) [55].

Many pharmaceutical and recreational drugs interact with serotonin receptors, such as antipsychotics, antidepressants, antiemetics, hallucinogens, anorectics, antiemetics antimigraine compounds, entactogens and gastroprokinetic agents [56].

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

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

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.

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.

The enzyme choline acetyltransferase carries out the acetylation of choline, in order to synthetize acetylcholine, which is a neurotransmitter of primary importance for the primary and peripheral nervous systems [57-61].

Acetylcholine receptors (AChRs) comprise two main classes, such as nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). In addition, there are five subtypes of muscarinic acetylcholine receptors: M1, M2, M3, M4 and M5 [62]. Nicotinic acetylcholine receptors contain five subunits that are arranged around a water-filled pore and belong to the “Cys-loop” superfamily of ligand-gated ion channels [63], whereas muscarinic acetylcholine receptors consist of a single protein with seven transmembrane domains, which bind acetylcholine in the extracellular component and with GTP-binding regulatory proteins (G proteins) in the intracellular moiety [64].

Nicotinic acetylcholine receptors are stimulated by nicotine and are expressed in postganglionic neurons in the sympathetic ganglia and in the adrenal medulla [65-68], whereas muscarinic acetylcholine receptors are present in the central nervous system, sweat glands of the skin, the lower urinary tract [69-71]. Interestingly, both nicotinic acetylcholine receptors and muscarinic acetylcholine receptors are also present in cells of the immune system, such as T and B cells, dendritic cells, and macrophages [72].

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.

The agonists and antagonists for nicotinic acetylcholine receptors and for muscarinic acetylcholine receptors are reported in Table 7.

Glutamate receptors are mainly expressed on the membrane of neuronal and glial cells [77] 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) (against NMDA glutamate receptor) [78], CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) (against AMPA/kainate glutamate receptor) [78], barbiturates, dextromethorphan, dextrorphan, dizocilpine, ibogaine, ifenprodil, ketamine, kynurenic acid, memantine, nitrous oxide, perampanel and phencyclidine.

GABA receptors are expressed in the mature central nervous system of vertebrates and comprise two classes: GABAA and GABAB receptors [79, 80].

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 [79, 80].

GABAA receptors agonists include: bamaluzole, gabamide, γ-Amino-β-hydroxybutyric acid (GABOB), gaboxadol, gaboxadol, ibotenic acid, isoguvacine, isonipecotic acid, muscimol [78], 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 (1(S),9(R)-(–)-bicuculline methiodide) [78], 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 [81].

GABAB receptors antagonists comprise the following drugs: 2-OH-saclofen, 2-phenethylamine, CGP-35348, CGP-52432, CGP-55845, ginsenosides [82], homotaurine [83], phaclofen, SCH-50911 and SGS-742 [84].

So far, no negative allosteric modulators have been identified for GABAB receptors [85].