Table 3.

Agonists of acetylcholine receptors (AChRs).

Agonists	Cholinergic effects	Effect of immune status	Experimental models
Pan-cholinergic agonists
Acetylcholine chloride	Non-selective cholinergic agonist mimics the effect of the endogenous compound acetylcholine.		Its multi-faceted action, toxicity, and rapid inactivation by cholinesterase do not offer a therapeutic value.
Carbachol	Non-selective cholinomimetic agonist stimulates both muscarinic and nicotinic receptors.	Carbachol treatment reduces the expression of IL-1β; MHC-II, CD86, and IL-12p70 in splenic DCs at the early phases of sepsis (138). It reduces the release of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and expression of caspase-3 in myocardial cells and improves the cardiac function and survival rate from sepsis in rats (139). Carbachol increases the expression of inflammatory genes (IL-6, IL-8, and cyclooxygenase-2)  in smooth muscles (140).	Used for treatment of glaucoma in humans (141).
Selective to nicotinic receptors
Nicotine	Nicotine induces non-selective activation of nAChRs.	Nicotine-treated cells produce lower Th1 cytokines (IL-2 and IFN-γ), but significantly higher Th2 cytokines (IL-4 and IL-10) (142). Nicotine suppresses IL-18-mediated systemic inflammatory responses and downregulates expression of TNF-α, IL-12, and IFN-γ in PBMCs (143).	Nicotine has anti-inflammatory and depressive activity in neurodegenerative and depressed patients (144, 145).
Cotinine	Activates, desensitizes nAChR at a much lower potency than nicotine.	A high cotinine concentration stimulates extracellular ROS generation and oxidative stress-mediated tissue damage by activated neutrophils (146). Pre-treatment of monocytes with cotinine mounts IL-10-dominated anti-inflammatory response via α7-nAChR through PI3K/GSK-3β-dependent pathway (147).
ABT-418		ABT-418 has a neuroprotective effect on rat cortical cells to glutamate (Glu)-induced cytotoxicity mediated via interaction with α7-nAChRs (148).	A clinical trial of ABT-418 was conducted to treat adults with attention deficit hyperactivity disorder and AD (149, 150).
Epibatidine	Binds to the α4/β2-nAChR and also binds to the α3/β4-nAChR subtype.	Stimulation of α4β2 nAChRs with epibatidine increases the IgM-mediated proliferation of B cells (151). In vivo administration of epibatidine (5 μg/kg, s.c.) increases plasma corticosterone levels and reduces the lymphocyte proliferation in the presence of concanavalin A (152).
Succinylcholine chloride	Irreversible and competitive agonist on muscle type (α1)2β1δϵ-nAChR (153). It is resistant to acetylcholinesterase and  is quickly degraded by plasma butyrylcholinesterase.	Patients who received succinylcholine as an anesthetic had lower CD4/CD8 frequency and IgE levels in their peripheral blood. It also changes the oxidative state of lymphocytes by impairing glutathione levels and prompting T cells to produce more reactive oxygen species (ROS) (154, 155).
PNU-282987	Selective α7-nAChR agonist	PNU-282987 has a protective function in the lung injury model. PNU−282987 inhibits TNF−α and IL−6 release and decreases the phosphorylation levels of p38, JNK, and ERK in peritoneal macrophages (156). In the bronchoalveolar microenvironment, PNU-282987 reduces the neutrophil recruitment and inflammatory cytokines secretion (157). It also has an anti-inflammatory role in NK cells by reducing the NF-κB levels and its translocation to the nucleus, down-regulating the expression of NKG2D receptors, and inhibiting IFN-γ secretion and NKG2D-dependent NK cell cytotoxicity (158)	It has been used as an anti-inflammatory therapy in animal models of diseases such as airway inflammation, cardiomyopathies, and AD (159–160).
Cris-104	Neuronal α4β2-nAChR agonist	Cris-104 increases nor-epinephrine concentration and increases neuronal activity in the brain, thus having an anti-nociceptive efficacy in rodent models of acute and chronic pain (161).
PHA-543613	Selective α7-nAChR agonist	PHA-543613 suppresses CDC42 and MMP2 mRNA expression in macrophages (162). Administration of PHA-543613 induces activation of PI3K/AKT/GSK-3β to reduce neuroinflammation and oxidative stress (163, 164).	It’s being studied as a potential cure for cognitive deficits in schizophrenia, PD, and intracerebral hemorrhage (165, 166).
NS6740	Silent non-ionotropic agonist of α7-nAChRs but an effective modulator of the cholinergic anti-inflammatory.	NS6740 shows an anti-inflammatory property in LPS challenge microglial cells by reducing TNF-α release (167).
GAT107	Positive modulator of α7-nAChR	GAT107 shows a dose‐dependently attenuation of CFA‐induced inflammatory pain by reducing phosphorylation of intracellular p38MAPK (168). In macrophages, GAT107  improves superoxide dismutase 1 activity, Nrf2, and hemeoxygenase-1 expression (169).
AR-R17779	Selective α7-nAChR agonist	AR-R17779 has a protective role mediated by α7-nAChR in intestinal colitis and post-operative infections model (170, 171). In CFA-induced arthritis, it plays a contradictory role. It decreased TNF-α levels in plasma and synovial tissue, as well as exacerbates arthritis (172, 173).
Nifene	Selective α4β2-nAChR receptor partial agonist		8F-Nifene is used in PET and SPECT imaging agents  to screen lung cancer (174).
Selective to muscarinic receptors
Muscarine	Non-selective agonist of the mAChR (175). It has both excitatory and inhibitory effect on ACh release at NMJ due to differential binding to various mAChRs.	Intravenous administration of muscarine chloride increases IgA secretion from the perfused intestinal loops in rats (176).
L-Satropane	mAChR agonists	L-satropane defends against CoCl2-induced neurotoxicity by increasing retinal neuron survival in a dose-dependent manner. L-satropane substantially reverses the Aβ production (177).
Oxotremorine (Oxo-M)	Non-selective (mAChR) agonists with positive allosteric modulation via M4 subtype.	Oxo-M promotes TCR/CD3ε-induced IL-2 secretion in human PBMCs. It also increases the cell surface expression of CD2, CD3, CD4, CD8, and IL-25 (178, 179) and promotes T cell proliferation (180).
McN-A-343	Selective M1 mAChR agonist, however, is partial agonist with a similar affinity at all five mAChR.	McN-A 343 therapy results in a substantial reduction in colitic score. McN-A-343 therapy reduced colonic inflammation and decreased pro-inflammatory Th1/Th17 colonic and splenic DC cytokine secretion mediated by the 7nAChR and NF-kB signaling pathways. CD4+ T cell priming was diminished after cholinergic activation (181)  McN-A-343 inhibits endotoxin-induced systemic TNF-α levels in a dose-dependent manner (182)
Cevimeline	Stimulates SSN neurons mainly by M1 mAChR and M3 mAChR.		Orally administered in the treatment of Sjogren’s syndrome (183).
Bethanechol chloride	Muscarinic agonist selectively activates M2 mAChR.	Suppresses tumorigenesis through MAPK and PI3K/AKT signaling (184). Bethanechol treatment of bone marrow-derived macrophages upregulates M3 mAChR gene expression and induces a classically-activated macrophage phenotype (185).	It has a bactericidal effect and increases intracellular cyclic GMP levels in the patient suffering from hidradenitis suppurativa (186). Administered to treat urinary retention and gastrointestinal motility (187, 188).
Arecaidine propargyl Ester (APE) and Arecaidine But-2-ynyl Ester Tosylate (ABET)	Highly selective M1 mAChR and M2 mAChR agonist.	APE treatment inhibits the proliferation of cancer stem cells in glioblastoma multiforme by lowering the expression of mir210 in hypoxia conditions (189).
7,8-dihydroxyflavone (7,8-DHF)	Positive allosteric modulator increased M3 mAChR.	It inhibits iNOS and COX-2 expression and reduces the synthesis of NO and PGE2. Besides, 7,8-DHF blocks the release and expression of inflammatory cytokines such as TNF-α and IL-1 (190, 191).	It shows a therapeutic efficacy for treating Alzheimer’s disease, Huntington’s disease, and schizophrenia in the animal model (192–193).
Amiodarone	Gq-mediated responses are positively modulated at M1 mAChR and M3 mAChR but inhibited in a more discriminating fashion at the M1 mAChR (194, 195).	TNF-α, IL-6, of IL-1β production, was inhibited by amiodarone at 0.1-1 µM concentration. Modulation of IL-6 and IL-1β production by amiodarone was biphasic and significantly increased at a concentration beyond 10 µM (196).	Amiodarone is an anti-arrhythmic drug used to treat several congestive heart failure (197, 198).
Xanomelin	M1/M4 mAChR preferring muscarinic agonist.	Xanomelin suppresses TNF-α and IL-6 levels and improves survival in an endotoxemia model. Treatment with ex vivo endotoxin-stimulated splenocytes shows significantly less sensitivity to inflammatory activation and lower secretion of TNF-α, IFN-γ, MCP1, IL-6, and IL-10 (199).	It was used in the treatment of both Alzheimer’s disease and schizophrenia (200–201).
Dihydroquinazolinone	Selective and CNS-penetrant M1 mAChR and M4 mAChR agonists.	It shows a potent inhibitor of p38alpha MAP kinase and suppresses TNF-α production in LPS-stimulated PBMCs (202).	–
Clozapine	Agonist at the M4 mAChR and antagonized agonist-induced responses at the other four mAChR.	Clozapine inhibits T-bet expression and promotes STAT6 and GATA3 expression in PBMCs (203). Clozapine therapy inhibits the production of IL-6, IL-8, and IL-12 and increases the production of IL-10 in LPS-stimulated macrophages (204). In neutrophils, clozapine increases cell surface Mac-1 expression and activates the AKT signaling pathway and phagocytosis of bacteria (205).	It is a highly effective antipsychotic medication (206).