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. 2023 May;191:106771. doi: 10.1016/j.phrs.2023.106771

Table 2.

Sig1R ligands with reported pro-convulsive and/or convulsive effects in preclinical animal models.

Compounds Administration (dose, route) Observations Affinity to Sig1R, Ki (nM) Additional targets, Ki (nM) References
Sig1R agonists
( ± )Alazocine
(( ± )SKF-10,047)		 Increasing cumulative i.v. doses of compound were given at 30-min intervals over a range of 0.1 – 51.2 mg/kg Convulsive activity: induced convulsions in female Sprague-Dawley rats (ED50 = 25.6 mg/kg, i.v.) 1800–4657 Kappa opioid R (0.4)
Mu opioid R (1.2)
Delta opioid R (IC50 = 184)
NMDA (2554)		 [90]
0.2 µmol or higher concentration, i.c.v. Convulsive activity:
induced diffuse clonic seizures in DBA/2 mice		 [92]
Citalopram 15 mg/kg i.p. 30 min before timed intravenous infusion of pilocarpine (24 mg/ml) at the constant infusion rate of 150 µl/min Pro-convulsive activity:
facilitated limbic seizures induced by pilocarpine in male NMRI mice		 167–404 SERT (0.5–33.0)
5-HT2C (156–617)
H1 (283–371)
Alpha1 (711–1820)
Ca2+ channels (996–1588)
5-HT2B (1171)
M1 (1430)
Na+ channels (2409)
NET (2178–6190)
TMEM97 (5410)
K+ channels (IC50 = 2600–3981)
DAT (9270)
5-HT2A (9500)		 [117]
25 and 50 mg/kg i.p. 30 min before PTZ (0.5%, i.v.) infusion (1 ml/min) Pro-convulsive activity:
significantly decreased seizure threshold in male NMRI mice		 [119]
25 and 50 mg/kg i.p. 30 min before PTZ (0.5%) i.v. infusion (1 ml/min) Pro-convulsive activity:
significantly decreased PTZ-induced seizure threshold in male NMRI mice		 [120]
82 and 122 mg/kg i.p. Convulsive activity:
induces seizures in Sprague-Dawley rats		 [296]
10 mg/kg/day s.c. delivered with osmotic minipumps for 4 weeks during amygdala kindling Pro-convulsive activity:
increased susceptibility to limbic epileptogenesis in male Wistar rats		 [297]
Dextromethorphan ((+)methorphan) More than 20 mg/kg bolus, or more than 10
mg/kg/h i.v.		 Convulsive activity:
male New Zealand white rabbits developed muscular tremor, focal motor seizures, hypotension, opisthotonic posturing and apnea		 10–652 SERT (1.4–40.0)
NET (240–6000)
nAChR (IC50 = 700–8900)
Alpha1 (830–3000)
Mu opioid R (1280)
Na+ channels (4800)
NMDAR (780–8945)
M1 (5070)
Kappa opioid R (7000)		 [298]
50 mg/kg p.o. 15 min before i.v. infusion of theophylline until the onset of maximal seizures Pro-convulsive activity:
after treatment with dextromethorphan a reduced convulsant dose
and concentration of theophylline was necessary to produce seizures in female Levis rats		 [299]
50 mg/kg p.o. 15 min before i.v. infusion of PTZ until the onset of maximal seizures Pro-convulsive activity:
significantly lower dose of the convulsant to produce maximal seizures in female Levis rats		 [299]
60 mg/kg i.p. 30 min before each daily stimulation in amygdaloid kindled seizure model Pro-convulsive activity:
potentiated development of amygdaloid kindling in male Sprague-Dawley rats		 [136]
60 mg/kg i.p. Convulsive activity:
produced spontaneous seizure activity in male Sprague-Dawley rats		 [136]
50 mg/kg i.p. 15 min before each daily stimulation in amygdaloid kindled seizure model Pro-convulsive activity:
accelerated the expression of kindled seizures in rats. Combination with phenytoin resulted in progressive seizure buildup		 [300]
50 and 75 mg/kg Pro-convulsive activity:
decreased NMDA-induced seizure threshold in rats		 [129]
30 mg/kg i.p. 30 min before stimulation in amygdaloid kindled seizure model Convulsive activity:
induced seizures in kindled female Wistar rats		 [128]
ED50 = 19 mg/kg i.v. Convulsive activity:
induced seizures in rats		 [301]
56 mg/kg i.p. Pro-convulsive activity:
increased sound-induced wild running in Wistar rat pups		 [144]
212 µmol/kg i.v. infusion Convulsive activity:
induced seizures in male Sprague-Dawley rats		 [302]
80 mg/kg i.p. Convulsive activity:
Sprague-Dawley rats showed increased seizure occurrence and intensity		 [303]
( ± )Fluoxetine 100 µM Pro-convulsive activity (in vitro):
increased seizure-like event frequency in preictal phase was observed in a low Mg2+/high K+ -induced seizure model in hippocampal slices which were isolated from male Wistar rat pups		 191–240 SERT (0.3–270.0)
Alpha2 (6–5012)
DAT (11–6670)
5-HT2C (50–398)
5-HT2A (55–1820)
Na+channel (82–90)
NET (85–6670)
M2 (512–2700)
Alpha1 (605–5260)
M1 (702–1030)
Ca2+ channels (736–1095)
M3 (762–3100)
5-HT6 (771–1770)
H1 (933–5400)
M5 (976–2070)
5-HT7 (1000)
TMEM97 (1610)
5-HT1A (1820–8310)
M4 (2090)
K+ channels (5012)
5-HT2B (5030)
5-HT1D (4270)
5-HT1B (6170)
H3 (7300)		 [158]
10 mg/kg i.p. for 21 days (the last administration was 1 h before the PTZ) Pro-convulsive activity:
reduced PTZ-induced (30 mg/kg, i.p.) seizure threshold and increased seizure severity in male Wistar rats.		 [304]
10 and 20 mg/kg i.p. 30 min prior to pilocarpine (400 mg/kg, s.c.) Pro-convulsive activity:
decreased the latency to first seizures, increased the number of seizures and decreased the survival in male rats		 [305]
10 mg/kg/day s.c. delivered with osmotic minipumps for 4 weeks during amygdala kindling Pro-convulsive activity:
increased susceptibility to limbic epileptogenesis in male Wistar rats		 [297]
30 mg/kg/day i.p. for 7 weeks in WAG/Rij rat model of
absence epilepsy		 Pro-convulsive activity:
pro-absence effect was observed after treatment of fluoxetine in 6-month old rats with established absence seizures		 [171]
15 mg/kg p.o. for 17 days Pro-convulsive activity:
increased seizure behavior and sudden death in male APPswe/PS1dE9
mice		 [306]
10 mg/kg/day s.c. for 30 days during amygdala kindling Pro-convulsive activity:
accelerated kindling epileptogenesis in male C57BL/6J (wild-type) and homozygous 5-HT2A knockout mice		 [307]
20 mg/kg i.p. 30 min after penicillin (500 IU, 2.5 µl) i.c. injection into the left sensorimotor cortex Pro-convulsive activity:
increased the frequency and amplitude of penicillin-induced epileptiform activity in male Wistar rats		 [173]
Fluvoxamine 40 mg/kg i.v. Convulsive activity:
caused some small spikes (EEG recording) in 2 out of 10 Wistar male rats		 17–36 DAT (1.5–9200)
SERT (1.5–540)
NET (299–5000)
Alpha1 (1290–4800)
Alpha2 (1900)
5-HT2C (5790–6700)
TMEM97 (8439)		 [308]
Ifenprodil
(erythro diastereomer)		 3.2, 10 and 32 µg, i.c.v. Pro-convulsive activity:
enhanced kindling in male Sprague-Dawley rats, biphasic dose-dependent effect was observed		 2–125 TMEM97 (5–98)
EBP (1)
NMDAR (8–94)
Alpha1 (12–140)
5-HT1A (46)
5-HT2B (66–95)
DAT (363)
5-HT2A (421–510)
5-HT7 (513)
5-HT2C (748)
Alpha2 (1600–2300)		 [183]
3 and 10 mg/kg i.p. 30 min before the priming of audiogenic seizures Pro-convulsive activity:
increased the incidence of wild-running in male and female Wistar rat pups (ED50 = 5.3 mg/kg, i.p.)		 [144]
Opipramol 5 and 10 mg/kg i.p. Pro-convulsive activity:
enhanced PTZ (30 mg/kg, i.p.) induced kindling in male Balb/c mice		 0.2–50.0 H1 (6)
EBP (13)
ERG2 (17)
TMEM97 (110)
5-HT2A (120)
D2 (120–300)
Alpha1 (200)
D1 (900)
H2 (4470)
Alpha2 (6100)		 [309]
( ± )Pentazocine 60 mg/kg i.p. Convulsive activity:
induced seizures in female Sprague-Dawley rats		 15–135 Kappa opioid R (2.2–75.0)
Mu opioid R (2.7–6.9)
Delta opioid R (49)
NMDAR (25–2820)
TMEM97 (1500–1900)
D2 (3500)		 [310]
3 mg/kg i.m. Pro-convulsive activity:
increased incidence of clonic-tonic seizures after the end of the PTZ (10 mg/kg per min, i.v.) infusion in dogs		 [311]
9 and 12 mg/kg i.v. Convulsive activity:
a characteristic pattern of unambiguous EEG and clinical signs of epilepsy in male Wistar rats were noticed 30 s after administration, responses were augmented by naloxone		 [312]
(+)Pentazocine 12.5, 25 and 50 mg/kg s.c. Pro-convulsive activity:
by 20–40% reduced threshold for flurothyl-induced seizures in male Sprague-Dawley rats		 1.5–42 TMEM97 (224–2060)
M1 (225)
M2 (525)
Mu opioid R (1700)
NMDAR (4190)		 [5]
(+)3-PPP 60–100 mg/kg i.p. Convulsive activity:
dose-dependently produced behavioral clonic and electrical (EEG) tonic-clonic seizures in CD-1 male mice		 6–75 D2 (9–776)
Mu opioid R (79)
TMEM97 (IC50 = 76–940)
D4 (130)
D3 (132–217)		 [313]
30 mg/kg i.p. given 30 min before the test Pro-convulsive activity:
significantly decreased the electroconvulsive threshold (auricular MES, 50 Hz, 0.2 s) in female Swiss mice, the effect was reversed by haloperidol		 [314]
Sig1R antagonists
NE-100 25 mg/kg i.p. 30 min before the i.v. infusion of PTZ Pro-convulsive activity:
significantly decreased PTZ-induced clonic seizure threshold in Swiss-Webster mice		 1.0–2.4 TMEM97 (85–212)
DAT (3600)
5-HT1A (IC50 = 6500)		 [210]
50 and 75 mg/kg i.p. Convulsive activity:
induced seizures in male Swiss-Webster mice		 [210]
75 mg/kg i.p. Convulsive activity: induced seizures in CD-1 background WT and Sig1R KO mice [18]
Rimcazole
(BW-234 U)		 5 and 10 mg/kg i.p. 30 min before the MES test Pro-convulsive activity:
significantly lowered the threshold for electroconvulsions in female Swiss mice, enhanced the protective activity of phenobarbital and valproate against MES		 97–2380 DAT (98–224)
TMEM97 (302)
SERT (825–1710)
Kappa opioid R (896)
NET (2160)
5-HT2A (5010)
D2 (7980–8700)		 [315]

Affinities of compounds were obtained from databases PubChem and Binding Database (accessed from May 25, 2022 till June 28, 2022). Table demonstrates the binding affinities (Ki) to targets of compounds at concentrations below 10 µM (< 1 ×10-5). NE-100: 4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine; 3-PPP: 3-(1-propylpiperidin-3-yl)phenol. MES – maximal electroshock-induced seizures; PTZ – pentylenetetrazole. Targets: Sig2R – sigma-2 receptor (known as TMEM97); EBP – emopamil binding protein; M1-M5 – muscarinic recepotrs; nAChRs – nicotinic actehylcholine receptors; Mu, Kappa, Delta – opioid receptor subtypes; NMDAR – N-methyl-D-aspartate receptors; NET – norepinephrine transporter; alpha-1 and alpha-2: adrenergic receptors; SERT – serotonin transporter; 5-HT1-7 – serotonin receptor subtypes; DAT – dopamine transporter; D1 and D2 – dopamine receptors; H1-3 – histamine receptors; Na+, K+ and Ca2+ - corresponding ion channels.