5-HT3 Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface

Gohar Fakhfouri; Reza Rahimian; Jonas Dyhrfjeld-Johnsen; Mohammad Reza Zirak; Jean-Martin Beaulieu

doi:10.1124/pr.118.015487

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Fig. 1.
Impact of 5-HT3R antagonists on the molecular pathways within different cell populations in the brain. Neural blockade by setrons of 5-HT₃R exerts neuroprotection by diminishing calcium influx and subsequent inhibition of the calcium-sensitive phosphatase calcineurin. The latter controls the activation status of transcriptional factors such as NFAT. Such inhibition affects the expression of proteins involved in survival and inflammation. Moreover, activation of 7α nAChR in neurons and glia by tropisetron triggers anti-inflammatory cascades, including JAK/STAT and PI3K/Akt, which potentiate the activity of transcriptional factor Nrf2 and its downstream pathways (HO-1 and CAT), and inhibits the canonical proinflammatory protein NFκB, which governs the production of proinflammatory cytokines (e.g., TNF-α) and enzymes (e.g., iNOS and COX-2) involved in neuroinflammation. Solid arrows indicate activation, blind-ended arrows indicate inhibition, and dashed arrows indicate activation of the target pathways in both cell types. CAT, catalase; COX-2, cyclooxygenase-2; eNOS, endothelial nitric oxide synthase; GSK3β, glycogen synthase kinase 3; HO-1, heme oxygenase-1; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; NFAT, nuclear factor of activated T cells; NFκB, nuclear factor κB; Nrf2, nuclear factor erythroid 2–related factor 2; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TNF-α, tumor necrosis factor α.
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Fig. 2.
Effects of 5HT₃R antagonists on neurotransmitter systems and the HPA axis.
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Fig. 3.
Advantageous therapeutic prolife of 5HT₃R antagonists over conventional medications prescribed for psychiatric disorders.

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TABLE 1

Compounds modulating 5-HT₃Rs

Drug or Compound	Species	Receptor Subtype	K_i, IC₅₀, or EC₅₀	Main Effect, Application, or Therapeutic Use	Reference
Agonist
5-HT	—	5-HT_3A	1.56–3.4 µM	Neurotransmitter	Thompson and Lummis, 2003
	N1E-115^{^a}	—	1.8 µM		Hussy et al., 1994
	SCG (mouse)	—	2.6 µM		Hussy et al., 1994
	NG108-15^{^b}	5-HT_3A	3.5 µM		Hussy et al., 1994
	Human^{^c}	5-HT_3A	123 nM		Hope et al., 1996
	Rat	—	219 nM		Steward et al., 1995
2-Methyl-5-HT	N1E-115^{^a}	—	11 µM	Derivative of serotonin	Hussy et al., 1994
	SCG (mouse)	—	11.8 µM		Hussy et al., 1994
	NG108-15^{^b}	5-HT_3A	13 µM		Hussy et al., 1994
	Human^{^c}	5-HT_3A	224 nM		Hope et al., 1996
	Human^{^c}	5-HT_3A	4.1 µM		Davies et al., 1999
	Rat	—	562 nM		Steward et al., 1995
m-CPBG	Mouse^{^d}	5-HT_3A	400 nM	Pharmacological tool	Downie et al., 1994
	Human^{^c}	5-HT_3A	19.5 nM		Hope et al., 1996
	Human^{^c}	5-HT_3A	480 nM		Dubin et al., 1999
	Rat	—	1.5 nM		Kilpatrick et al., 1990
	Rat	—	4.77 nM		Steward et al., 1995
Phenylbiguanide	Mouse^{^d}	5-HT_3A	18 µM	Pharmacological tool	Downie et al., 1994
	NG 108-15^{^b}	—	1.2 µM		Dukat et al., 1996
	NG 108-15^{^b}	—	1.8 µM		Downie et al., 1995
	Human^{^c}	5-HT_3A	2.4 µM		Hope et al., 1996
	Human^{^c}	5-HT_3A	10.1 µM		Dubin et al., 1999
	Rat	—	135 nM		Steward et al., 1995
Varenicline	Human^{^d}	5-HT_3A	5.9 μM	Used for smoking cessation	Lummis et al., 2011
	Human^{^c}	5-HT_3A	0.27 μM
	Mouse^{^d}	5-HT_3A	18.3 μM
	Human^{^c}	5-HT_3A	4.9 μM
m-CPP	Mouse	5-HT_3A	400 nM	Nonselective agonist with psychoactive properties	Downie et al., 1994
	Human^{^d}	5-HT_3A	480 nM		Dubin et al., 1999
	Human^{^d}	5-HT_3A	19.5 nM		Hope et al., 1996
	Rat	—	4.77 nM		Steward et al., 1995
Quipazine	Human^{^d}	5-HT_3A	27 nM	Piperazine analog with antidepressant and oxytocic properties	Dubin et al., 1999
Dopamine	Human^{^d}	5-HT_3A	135 μM	Neurotransmitter	Dubin et al., 1999
2-Chloro-phenylbiguanide	NG 108-15^{^b}	—	62 nM	—	Dukat et al., 1996
3-Chloro-phenylbiguanide	NG 108-15^{^b}	—	17 nM	—	Dukat et al., 1996
4-Chloro-phenylbiguanide	NG 108-15^{^b}	—	200 nM	—	Dukat et al., 1996
2-Naphthylbiguanide	NG 108-15^{^b}	—	12 nM	—	Dukat et al., 1996
2-Methoxy-5-chloro-phenylpiperazine-	NG 108-15^{^b}	—	40 nM	—	Dukat et al., 1996
3,4-Dichlorophenylguanidine	NG 108-15^{^b}	—	3.1 nM	—	Glennon et al., 2003
3,4,5-Trichlorophenylbiguanide	NG 108-15^{^b}	—	0.7 nM	—	Glennon et al., 2003
3,4-Dichlorophenylbiguanide	NG 108-15^{^b}	—	3.1 nM	—	Glennon et al., 2003
N-Methylquipazine dimaleate	Rat	—	4.7 nM	—	Glennon et al., 1989
RS 56812 hydrochloride	Rat	—	—	—	Clark et al., 1995
SR 57227A	Rat	—	2.8 nM	Pharmacological tool	Bachy et al., 1993
	NG 108-15^{^b}	—	250 nM		Bachy et al., 1993
Competitive antagonists
Granisetron	Mouse^{^d}	5-HT_3A	0.14 nM	Antiemetic used for CINV	Downie et al., 1994
	Human^{^c}	5-HT_3A	1.44 nM		Hope et al., 1996
	N1E-115^{^a}	—	0.23 nM		Lummis et al., 1993
	Rat	—	5.13 nM		Steward et al., 1995
Tropisetron	NG 108-15^{^b}	—	3.85 nM	Antiemetic used for CINV	Downie et al., 1995
	Rat	—	4.9 nM		Steward et al., 1995
	Rabbit	—	0.046 nM		Peters et al., 1993
Ondansetron	Mouse^{^d}	5-HT_3A	0.44 nM	Antiemetic used for CINV	Gill et al., 1995
	Human^{^c}	5-HT_3A	4.9 nM		Hope et al., 1996
	N1E-115^{^a}	—	7.4 nM		Lummis et al., 1990
	Mouse (NCB-20 cells)	—	0.25 nM		Lambert et al., 1989
	Rat	—	46.8 nM		Steward et al., 1995
	Rabbit	—	0.057 nM		Peters et al., 1993
Dolasetron	NG 108-15^{^b}	—	20.03 nM	Antiemetic	Boeijinga et al., 1992
Azasetron	Rat	—	2.9 nM	Antiemetic	Sato et al., 1992
Ramosetron	Human^{^c}	—	0.091 nM	Antiemetic, also used for IBS	Hirata et al., 2007
	Rat	—	0.22 nM		Hirata et al., 2007
Alosetron	Guinea pig	—	50 nM	Used for IBS-D	Zhai et al., 1999
	Human^{^c}	—	0.29 nM		Hirata et al., 2007
	Rat	—	0.71 nM		Hirata et al., 2007
Cilansetron	Human^{^c}	—	0.56 nM	Used for IBS-D	Hirata et al., 2007
	Rat	—	0.64 nM		Hirata et al., 2007
Palonosetron (RS 25259-197)	Guinea pig	—	5.01 nM	Antiemetic used for delayed CINV	Thompson and Lummis, 2007
Indisetron	Rat	—	1.82 nM	Antiemetic	Taniguchi, 2004
Bemesetron (MDL-72222)	N1E-115^{^a}	—	16 nM	Antiemetic	Lummis et al., 1990
	N1E-115^{^a}	—	3.5 nM		Hussy et al., 1994
	SCG (mouse)	—	5 nM		Hussy et al., 1994
	NG108-15^{^b}	5-HT_3A	3.5 nM		Hussy et al., 1994
	Rat	—	30.2 nM		Steward et al., 1995
	Rabbit	—	0.33 nM		Peters et al., 1993
Mirtazapine	Human^{^c}	5-HT_3A	2.9 nM	Atypical antidepressant	Eisensamer et al., 2003
Zacopride	Human	—	0.38 nM	Antiemetic, gastroprokinetic, and anxiolytic	Nagakura et al., 1999
(S)-Zacopride	Rat	—	0.95 nM		Steward et al., 1995
(R)-Zacopride	Rat	—	10.9 nM		Steward et al., 1995
Renzapride	Rat	—	67.6 nM	Antiemetic	Steward et al., 1995
Clozapine	Rat	—	269 nM	Atypical antipsychotic	Steward et al., 1995
Chloroquine	Human^{^d}	5-HT_3A	24.3 μM	Antimalarial agent	Thompson and Lummis, 2008
Mefloquine	Human^{^d}	5-HT_3A	0.66 μM		Thompson and Lummis, 2008
Quinine	Human^{^d}	5-HT_3A	1.06 μM		Thompson and Lummis, 2008
Diltiazem	N1E-115^{^a}	5-HT_3A	5.5 nM	L-type calcium channel blocker, used for hypertension, angina, and some heart arrhythmias	Gunthorpe and Lummis, 1999
	Human^{^d}	5-HT_3A	21 µM		Thompson et al., 2011a
(+)-Verapamil	N1E-115^{^a}	5-HT_3A	2.6 nM		Hargreaves et al., 1996
(−)-Verapamil	N1E-115^{^a}	5-HT_3A	13.1 nM		Hargreaves et al., 1996
Cannabidiol	Human^{^d}	5-HT_3A	0.6 nM	Nonpsychotropic cannabinoid	Yang et al., 2010
Poria cocos triterpenoids	Human^{^d}	5-HT_3A	3 nM	Medicinal plant used for chronic gastritis, edema, nephritis, nausea, and emesis	Lee et al., 2009
Boldine	Human^{^c}	5-HT_3A	5.5 µM	Aporphine alkaloid from Peumus boldus leaves with antioxidant properties	Walstab et al., 2014
	Human^{^c}	5-HT_3AB	35.5 µM		Walstab et al., 2014
Morphine	Human^{^c}	5-HT_3A	13 µM	Opioid analgesic	Baptista-Hon et al., 2012
	Human^{^c}	5-HT_3AB	8 µM		Baptista-Hon et al., 2012
Scopolamine	Human^{^c}	5-HT_3A	2.09 μM	Muscarinic antagonist used for postoperative nausea and vomiting and motion sickness	Lochner and Thompson, 2016
Atropine	Human^{^c}	5-HT_3A	1.74 μM	Muscarinic antagonist used as cycloplegic and mydriatic, also for bradycardia	Lochner and Thompson, 2016
Quercetin	Human^{^d}	5-HT_3A	64.7 μM	Flavonoid with analgesic, prokinetic, anticonvulsant, sedative, and anxiolytic properties	Lee et al., 2005a
Noncompetitive antagonists
Alisol extract	Human^{^d}	5-HT_3A	1.7–35 μM	Traditional medicine with diuretic, hypolipemic, antiatherosclerotic, and antihepatitis B virus properties	Lee et al., 2010
Anandamide	Human^{^c}	5-HT_3A	129.6 nM	Endocannabinoid	Barann et al., 2002
Δ9-THC	Human^{^c}	5-HT_3A	38.4 nM	Main psychoactive component of cannabis	Barann et al., 2002
WIN55,212-2	Human^{^c}	5-HT_3A	103.5 nM	Synthetic, nonselective cannabinoid	Barann et al., 2002
Bilobalide	Human^{^d}	5-HT_3A	468 μM	Noncompetitive antagonist of GABA and glycine receptors	Thompson et al., 2011a
	Human^{^d}	5-HT_3AB	3100 μM		Thompson et al., 2011a
Ginkgolide B	Human^{^d}	5-HT_3A	727 μM		Thompson et al., 2011a
	Human^{^d}	5-HT_3AB	3900 μM		Thompson et al., 2011a
Picrotoxinin	Human^{^d}	5-HT_3A	11 μM		Thompson et al., 2011a
	Human^{^d}	5-HT_3AB	62 μM		Thompson et al., 2011a
Picrotoxin	Mouse^{^c}	5-HT_3A	41.2 μM	GABA_A receptor antagonist	Das and Dillon, 2005
Citral	Human^{^d}	5-HT_3A	120 µM	Terpenoid used as flavoring agent	Jarvis et al., 2016
Linalool	Human^{^d}	5-HT_3A	141 µM		Jarvis et al., 2016
Eucalyptol	Human^{^d}	5-HT_3A	258 µM		Jarvis et al., 2016
(−)-Menthol	Human^{^c}	5-HT_3A	179.41 µM	Monoterpene from mentha used as flavoring agent	Walstab et al., 2014
Ginger extract	Human^{^c}	5-HT_3A	74.9 nM	Traditional medicine used for spa	Walstab et al., 2013
	Human^{^c}	5-HT_3AB	77.2 nM		Walstab et al., 2013

Dashes indicate not identified or not applicable. CINV, chemotherapy-induced nausea and vomiting; IBS-D, diarrhea dominant IBS; m-CPP, meta-chlorophenylpiperazine; SCG, superior cervical ganglion.
↵^a Mouse neuroblastoma cells.
↵^b Mouse neuroblastoma × rat glioma hybrid cells.
↵^c Expressed in human embryonic kidney 293 cells.
↵^d Expressed in Xenopus laevis oocytes.

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TABLE 2

Proconvulsant effects reported with 5-HT₃R ligands

Category	Compound, Dose, Route of Administration	Study Design	Effects	Proposed Mechanism	Reference
5-HT₃R agonist	Bemesetron (MDL-72222) (0, 5.6, 10, and 17.0 mg/kg, i.p.)	Ethanol withdrawal-induced seizure in mice	Potentiates severity of seizures	Inhibits GABA-activated chloride channels	Grant et al., 1994
	m-CPBG (40 µg, i.c.v.)	Kindling model of epilepsy in rats	Prolongs the duration of fully kindled seizures, facilitates the development of seizure	5-HT₃Rs activation mediates a fast excitatory postsynaptic potential in the amygdala	Wada et al., 1997
5-HT₃R antagonist	Granisetron (10 mg/kg, i.p.)	PTZ-induced seizure in mice	Decreases seizure threshold	Blockade of 5-HT₃R–mediated cation conductance in GABAergic interneurons disinhibits excitatory postsynaptic neurons	Gholipour et al., 2010
	Ondansetron (0.13 mg/kg, i.v.)	Case report in a child	Develops generalized tonic-clonic seizures, reduces blood glucose level to 10 mg/dl	—	Patel et al., 2011
	Ondansetron (2 mg/kg, i.p.)	PTZ-induced kindling model of epilepsy in mice	Partially reverses the anticonvulsant action and neuroprotective effect of fluvoxamine	Anticonvulsant effect of fluvoxamine, at least in part, depends on enhancement of hippocampal serotoninergic transmission at 5-HT₃Rs	Alhaj et al., 2015
	Tropisetron (1 mg/kg, i.p.)	PTZ-induced seizure in mice	Inhibits the anticonvulsant effect of citalopram	Blockade of the 5-HT₃R as a calcium-conducting ion channel results in inhibition of early depolarization of inhibitory interneurons	Payandemehr et al., 2012
	Tropisetron (10 mg/kg, i.p.)	PTZ-induced seizure in mice	Offsets the anticonvulsant effect of genistein	Estrogen and 5-HT₃Rs are involved in the anticonvulsant effect of genistein	Amiri Gheshlaghi et al., 2017
	Tropisetron (0.25 and 2 mg/kg, i.p.)	PTZ-induced seizure in mice	Inhibits the anticonvulsant properties of citalopram	Anticonvulsive effect of citalopram is mediated at least in part through 5-HT₃Rs	Bahremand et al., 2011

Dashes indicate not identified or not applicable.

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TABLE 3

Anticonvulsant effects reported with 5-HT₃R ligands

Category	Compound, Dose, Route of Administration	Study Design	Effects	Proposed Mechanisms	Reference
5-HT₃R agonists	m-CPBG (5 and 10 mg/kg, i.p.)	PTZ-induced seizure in mice	Potentiates the anticonvulsant effect of low doses of citalopram	5-HT₃R activation increases firing of interneurons and subsequent GABA release	Payandemehr et al., 2012
	m-CPBG (1 mg/kg, i.p.)	PTZ-induced seizure in mice	Potentiates the anticonvulsant effect of genistein	5-HT₃R is involved in the anticonvulsant effect of genistein	Amiri Gheshlaghi et al., 2017
	SR 57227 (20–40 mg/kg, i.p.)	PTZ-induced seizure in mice	Anticonvulsant; prolongs seizure latency, reduces seizure score and mortality	5-HT₃R activation may result in GABA release in the hippocampus	Li et al., 2014
	SR57227 (10 mg/kg, i.p.)	PTZ-induced seizure threshold in mice	Increases seizure threshold	5-HT₃ activation may result in GABA release	Gholipour et al., 2010
5-HT₃R antagonists	HBK-15 (20, 30, and 40 mg/kg, i.p.)^{^a}	Maximal electroshock-induced seizure in mice	Increases the threshold for tonic seizures	Combined antagonistic action at 5-HT_1A/5-HT₃/5-HT₇ receptors and voltage-dependent sodium channels	Pytka et al., 2017
	Ondansetron (0.1, 0.5, and 1 mg/kg per day for 20 days, i.p.)	PTZ-induced kindling in mice	Reduction in seizure severity and associated memory deficit in a dose-dependent manner	Reduction in AChE activity and nitrite level in the cortex and hippocampus	Mishra and Goel, 2016
	Ondansetron (0.1, 0.5, and 1 mg/kg per day, i.p.)	Increasing current electroshock seizure in mice	Single dose and chronic administration raise the seizure threshold, chronic treatment enhances cognitive performance	Change in the influx of cations, leading to the inhibition of neuronal depolarization	Jain et al., 2012
	Ondansetron (0.25–4 mg/kg, i.p.)	Maximal electroshock-induced seizure in rats	Decreases the duration of tonic seizures at low doses, attenuates phenytoin-induced cognitive dysfunction	Facilitation of cholinergic transmission in brain	Balakrishnan et al., 2000
	Zacopride (1 mg/kg, i.p.)	Audiogenic seizure in DBA/2 mice	Increases seizure latency and decreases seizure severity	Alteration of brain 5-HT content, densities of 5-HT binding sites, and/or sensitivity to 5-HT receptor agonists	Semenova and Ticku, 1992