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

Table 1.

Preclinical anti-seizure effects of Sig1R ligands.

Compound and affinity to Sig1R (nM)	Additional targets < 10 µM (Ki, nM)	Effective dose	Administration route, time before the seizures	Animals	Seizure model	References
Sig1R agonists
( ± )Alazocine (( ± )SKF-10,047) K_i= 1800–4700	Kappa opioid R (0.4) Mu opioid R (1.2) Delta opioid R (IC₅₀ = 184) NMDA (2554)	ED₅₀ = 2.4–6.1 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
		10–40 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	Flurothyl (10%)	[5]
		10–40 mg/kg	i.p., 20 min	Male Sprague-Dawley rats	Amygdala-kindling	[88]
		0.1–10 mg/kg	s.c., 20 min	Male and female genetically sensitive Mongolian gerbils	Sensory-evoked epileptic seizures	[89]
		5 and 20 mg/kg	i.p., 15 min	Female Sprague-Dawley rats	MES (corneal)	[90]
		50 mg/kg	i.p., 10 min	Male Sprague-Dawley rats	Hyperbaric pressure-induced neurological syndrome	[91]
		ED₅₀ = 50 nmol (i.c.v.); ED₅₀ = 24–69 µmol/kg (i.p.)	i.c.v., 15 min; i.p., 15–45 min	Male and female DBA/2 mice	Sound (109 dB)	[92]
		20 mg/kg	i.p., 40 min	Male C57BL/6J mice	MES-T (auricular)	[93]
		20 mg/kg	i.p., 40 min	Male C57BL/6J mice	PTZ (80 mg/kg, s.c.)	[93]
		20 mg/kg	i.p., 40 min	Male C57BL/6J mice	Kainic acid (30 mg/kg, i.p.)	[93]
(+)Alazocine ((+)SKF-10,047) K_i= 45–153	NMDA (587) Kappa opioid R (1600) Mu opioid R (1900) TMEM97 (IC₅₀ = 4543)	1–30 mg/kg	i.p., 10 min	Male Swiss-Webster mice	PTZ (125 mg/kg/ s.c.)	[94]
		ED₅₀ = 7.1 mg/kg	s.c., 30 min	Male CF-1 mice	MES (corneal)	[95]
		ED₅₀ = 17.4 mg/kg	i.v., 15 min	Male Swiss-Webster mice	NMDLA (500 mg/kg, s.c.)	[96], [97]
		ED₅₀ = 1.5 mg/kg	s.c.	Male Sprague-Dawley rats	MES (auricular)	[98]
		ED₅₀ = 28.2 mg/kg	s.c., 30 min	Male Swiss-Webster mice	NMDLA (500 mg/kg, s.c.)	[99]
		0.3–5.6 mg/kg	i.p., 15 min	Male C57BL/6J mice	(-)Cocaine (100 mg/kg, i.p.)	[100]
ANAVEX1–41 (AE14) K_i= 44	M1 (19) M3 (50) M4 (77) M2 (114) TMEM97 (3924)	19 mg/kg	p.o.	Mice	PTZ	[101]
ANAVEX1–41 (AE14) K_i= 44	M1 (19) M3 (50) M4 (77) M2 (114) TMEM97 (3924)	45 mg/kg	p.o.	Mice	MES	[101]
Blarcamesine (ANAVEX®2–73, AE37) IC₅₀= 860	M1-M4 (IC₅₀ = 3300–5200) Na⁺ channel (5100) NMDA (8000)	30 and 100 mg/kg	i.p., 1 h	Swiss male mice	MES	[102], [103]
		30 and 100 mg/kg	i.p., 1 h	Swiss male mice	PTZ (130 mg/kg, i.p.)	[102], [103]
		15, 30 and 60 mg/kg	i.p., 1 h	Swiss male mice	Semicarbazide	[102]
Caramiphen K_i= 16–26	M1 (1.2) M2 (32) nAchR (IC₅₀ = 300) DAT (5180–5250)	ED₅₀ = 5.7–14.0 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
		IC₅₀ = 46 µM	in vitro	Male Wistar rats	Mg²⁺-free model in hippocampal slices	[104]
		ED₅₀ = 14 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	MES (auricular)	[105]
		100 mg/kg	i.m.	Guinea pigs	Soman (2 x LD₅₀)	[106]
		ED₅₀ = 52 mg/kg	i.p., 30 min	Male NSA/CF1 mice	MES (auricular)	[107]
		ED₅₀ = 1.5 mg/kg	i.m., 30 min	Male Crl CDBR Vaf/Plus Sprague-Dawley rats	Soman (180 µg/kg = 1.6 × LD₅₀, s.c.)	[108]
		ED₅₀ = 3.1 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	MES (auricular)	[109]
		ED₅₀ = 7.8 mg/kg	i.v., 10 min	Shanghai mice	Nicotine (1 mg/kg, i.v.)	[110]
		20 mg/kg	i.m., 5, 10 and 20 min (after)	Male Sprague-Dawley rats	Sarin (108 mg/kg = 1.2 × LD₅₀, i.m.)	[111]
		100 mg/kg	i.m., 30 and 60 min (after)	Male Sprague-Dawley rats	Soman (154 µg/kg = 1.4 × LD₅₀, s.c.)	[112]
		20 mg/kg	i.m., 10 min	Male Sprague-Dawley rats	Soman (132 μg/kg, s.c.)	[113]
*Carbetapentane (Pentoxyverine) K_i= 10–129	5HT3A (8–165) M1 (76) M2 (167) Alpha1 (IC₅₀ = 1550) TMEM97 (56–1953) DAT (3090)	ED₅₀ = 10.2–38.2 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
		IC₅₀ = 38 µM	in vitro	Wistar rats	Mg²⁺-free model in hippocampal slices	[104]
		ED₅₀ = 4.8 mg/kg	s.c.	Male Sprague-Dawley rats	MES (auricular)	[114]
		ED₅₀ = 48 µmol/kg	s.c., 30 min	Male Sprague-Dawley rats	MES (auricular)	[105]
		ED₅₀ = 215.3 mg/kg (p.o.); ED₅₀ = 45 mg/kg (i.p.)	p.o. and i.p., 30 min – 4 h	Male CF-1 mice	MES (corneal)	[115]
		-	-	Guinea pigs	Soman (2 x LD₅₀)	[106]
		ED₅₀ = 10 mg/kg	i.m., 30 min	Male Crl CDBR Vaf/Plus Sprague-Dawley rats	Soman (180 µg/kg = 1.6 × LD₅₀, s.c.)	[108]
		* 12.5 and 25 mg/kg	i.p., 30 min	Male Sprague-Dawley rats	Kainic acid (10 mg/kg, i.p.)	[116]
( ± )Cyclazocine K_i= 36–47	Kappa opioid R (0.1–0.2) Mu opioid R (0.2–0.3) Delta opioid R (2.0) NOP R (157–7500)	ED₅₀ = 0.4–0.7 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
( ± )Cyclazocine K_i= 36–47		1–10 mg/kg	i.p., 20 min	Male Sprague-Dawley rats	Amygdala-kindling	[88]
(+)Cyclazocine K_i= 17	Kappa opioid R (0.1–0.2) Mu opioid R (0.1–0.3) Delta opioid R (1.1)	5 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	Flurothyl (10%)	[5]
Citalopram K_i= 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)	30, 100 and 300 µM	in vitro	Zebrafish (Tg(fli1a:EGFP)y1)	PTZ (40 mM)	[117]
		30, 100 and 300 µM	in vitro	Zebrafish (Tg(fli1a:EGFP)y1)	Pilocarpine (20 mM)	[117]
		1 and 10 µM	i.c.	Male Wistar rats	Pilocarpine (intra-hippocampal perfusion with 10 mM pilocarpine for 40 min)	[118]
		1 mg/kg	i.p., 30 min	Male NMRI mice	PTZ (0.5%, i.v. infusion)	[119], [120]
		15 mg/kg	i.p. for 4 days (after)	Male Sprague-Dawley rats	Kainic acid (5 mg/kg, i.p. repeatedly)	[121]
		20 mg/kg	i.p., 30–60 min	Male and female C57BL/6J mice	Amygdala-kindling	[122]
*Dextrorphan K_i= 118–481	SERT (401–484) NET (340) Mu oioid R (420) NMDAR (486–906) Kappa opioid R (5950)	1–250 µM	in vitro	Guinea pigs	Mg²⁺-free model in neocortical brain slices	[123]
		ED₅₀ = 3.5–5.6 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
		IC₅₀ = 1.5 µM	in vitro	Male Wistar rats	Mg²⁺-free model in hippocampal slices	[104]
		ED₅₀ = 12 µmol/kg	s.c., 30 min	Male Sprague-Dawley rats	MES (auricular)	[124]
		ED₅₀ = 102 µmol/kg	i.p., approx. 30 min	Male CF-1 mice	NMDA (250 mg/kg, i.p.)	[125]
		ED₅₀ = 35 nmol (i.c.v.); ED₅₀ = 19–37 µmol/kg (i.p.)	i.c.v., 15 min; i.p., 15–45 min	Male and female DBA/2 mice	Sound (109 dB)	[92]
		ED₅₀ = 9.6 mg/kg	s.c., 30 min	Male CF-1 mice	MES (corneal)	[95]
		30 mg/kg	i.p., 30 min	Female SPF-Fu mice	NMDA (1 nmol/µl, i.c.v.)	[126]
		ED₅₀ = 1.9 mg/kg	i.v., 15 min	Male ddY mice	NMDA (2 nmol, i.c.v.)	[127]
		ED₅₀ = 5.5 mg/kg	i.v., 15 min	Male ddY mice	AMPA (16 nmol, i.c.v.)	[127]
		ED₅₀ = 2.2 mg/kg	i.v., 15 min	Male ddY mice	Kainic acid (4 nmol, i.c.v.)	[127]
		ED₅₀ = 2.7 mg/kg	i.v., 15 min	Male ddY mice	BIC (2 nmol, i.c.v.)	[127]
		ED₅₀ = 6.9 mg/kg	i.v., 15 min	Male ddY mice	PTZ (20 µmol, i.c.v.)	[127]
		30 mg/kg	i.p., 15 min	Female Wistar rats	Amygdala-kindling	[128]
		25 and 50 mg/kg	-	Rats	NMDA	[129]
		ED₅₀ = 31 mg/kg	30 min	Female NMR mice	MES (corneal)	[130]
		12.5 and 25 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	Kainic acid (10 mg/kg, i.p.)	[131]
		* 10 µg/0.5 µl	i.c.v.	Male DBA/2 mice	Kainic acid (0.07 µg/0.07 µl, i.c.v.)	[132]
		ED₅₀ = 20 mg/kg	i.p., 20 min	Male Sprague-Dawley rats	MES	[133]
		ED₅₀ = 5 µg	i.c.v., 15 min	Male Sprague-Dawley rats	NMDA (12.5 nM, i.c.v.)	[134]
*Dextromethorphan K_i= 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)	100 µM	in vitro	Guinea pigs	Mg²⁺-free model in neocortical brain slices	[123]
		ED₅₀ = 11–15 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
		ED₅₀ = 6.2 mg/kg	s.c.	Male Sprague-Dawley rats	MES (auricular)	[114]
		35 mg/kg	i.p., 30–45 min	Male Sprague-Dawley rats	Amygdala-kindling	[135]
		ED₅₀ = 106 µmol/kg	i.p., approx. 30 min	Male CF-1 mice	NMDA (250 mg/kg, i.p.)	[125]
		ED₅₀ = 11.8 mg/kg	s.c., 30 min	Male CF-1 mice	MES (corneal)	[95]
		ED₅₀ = 93.9 mg/kg (p.o.); ED₅₀ = 45.7 mg/kg (i.p.)	p.o. and i.p., 30 min – 4 h	Male CF-1 mice	MES (corneal)	[115]
		ED₅₀ = 70 nmol (i.c.v.); ED₅₀ = 28–36 µmol/kg	i.c.v., 15 min; i.p., 15–45 min	Male and female DBA/2 mice	Sound (109 dB)	[92]
		10 mg/kg	i.p., 30 min	Female SPF-Fu mice	NMDA (1 nmol/µl, i.c.v.)	[126]
		-	-	Guinea pigs	Soman (2 x LD₅₀)	[106]
		ED₅₀ = 59 mg/kg	i.p., 30 min	Male Sprague-Dawley rats	Amygdala-kindling	[136]
		-	-	Mice	NMDLA	[137]
		-	-	Mice	PTZ	[137]
		-	-	Mice	MES	[137]
		ED₅₀ (clonus) = 161 µmol/kg	i.p., 60 min	Genetically epilepsy-prone rats (GEPR-9 s)	Sound (109 dB)	[138]
		7.5–15 mg/kg	i.p., 30 min	Female Wistar rats	Amygdala-kindling	[128]
		ED₅₀ = 20 mg/kg	i.p., 30 min	Male CD-1 mice	NMDA (0.8 µg/mouse, i.c.v.)	[139]
		ED₅₀ = 38.6 mg/kg	30 min	Female NMR mice	MES (corneal)	[130]
		12.5–75 mg/kg	p.o., 15 min	Rats	Kainic acid	[140]
		50 and 75 mg/kg	p.o., 15 min	Male Fischer rats	Kainic acid (8 mg/kg, i.p.)	[141]
		10, 20 and 40 mg/kg	i.p., 3 h	Male Wistar rats	Sound (100 dB)	[142]
		0.2 mg/kg	i.p., 25 min	Female mice	Theophylline (300 mg/kg, i.p.)	[143]
		ED₅₀ = 7.94 mg/kg	i.p., 30 min	Wistar rat pups	Sound (122–125 dB)	[144]
		12.5 and 25 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	Kainic acid (10 mg/kg, i.p.)	[131]
		12.5 and 25 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	BAY k-8644 (37.5 µg, i.c.v.)	[131]
		* 5 and 10 µg/0.5 µl	i.c.v.	Male DBA/2 mice	Kainic acid (0.07 µg/0.07 µl, i.c.v.)	[132]
		ED₅₀ = 25 mg/kg	i.p., 20 min	Male Sprague-Dawley rats	MES	[133]
		12.5 mg/kg	i.p., 30 min	Mice	BAY k-8644 (37.5 µg, i.c.v.)	[145]
		* 12 and 24 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	Kainic acid (10 mg/kg, i.p.)	[146]
		25 mg/kg	s.c., 30 min	Male Fischer 344 rats	Trimethyltin (8 mg/kg, i.p.)	[147]
		10, 30 and 100 mg/kg	i.p., 30 min	Male NMRI mice	PTZ (i.v. infusion)	[148]
		25 and 50 mg/kg	i.p., 30 min	Male NMRI mice	PTZ (i.v., 5 mg/ml at a rate of 0.5 ml/min)	[149]
		25 mg/kg	s.c., from postnatal day 8–21	C57BL/6NJ background Grin2a knock-in mice	Spontaneous seizures	[150]
		ED₅₀ = 168 µg	i.c.v., 15 min	Male Sprague-Dawley rats	NMDA (12.5 nM, i.c.v.)	[134]
*Dimemorfan K_i= 151	TMEM97 (4421)	ED₅₀ = 70 µmol/kg	i.p., 30 min	Male ICR mice	MES (corneal)	[151]
		6.25 and 12.5 mg/kg	i.p., 30 min	Mice	BAY k-8644 (37.5 µg, i.c.v.)	[145]
		* 12 and 24 mg/kg	s.c., 30 min	Male Sprague-Dawley rats	Kainic acid (10 mg/kg, i.p.)	[146]
Ditolylguanidine (DTG) K_i= 15–208	TMEM97 (12–107) M1 (744) VAChT (1134) ERG2 (2000) M2 (2960) Opioid R (3950) NMDAR (6690) EBP (6700)	ED₅₀ = 4.7–18.4 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
		IC₅₀ = 15 µM	in vitro	Male Wistar rats	Mg²⁺-free model in hippocampal slices	[104]
		ED₅₀ = 5.25 nM	i.c.	Rats	BIC (i.c.)	[152]
Donepezil K_i= 15	AChE (2–38) BchE (IC₅₀ = 20–15240) BACE1 (IC₅₀ = 169–3200) H3 (IC₅₀ = 350) K⁺ channels (IC₅₀ = 1995) BuChE (2140)	2.5 mg/kg	p.o. for 3 weeks (after)	Male Sprague-Dawley rats	Pilocarpine (25 mg/kg, i.p.)	[153]
		5.6 mg/kg	i.p., 1 h	Male CF1 mice, C56Bl/6 J background male and female heterozygous Scn1a knockout (Scn1a+/-) mice	MES (corneal)	[154]
		5.6 mg/kg	i.p., 1 h	Male and female C56Bl/6 J background heterozygous Scn1a knockout (Scn1a+/-) mice	PTZ (100 mg/kg, i.p.)	[154]
( ± )Fluoxetine K_i= 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) AchE (130) 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) Sig2R (1610) 5-HT1A (1820–8310) M4 (2090) K⁺ channels (5012) 5-HT2B (5030) 5-HT1D (4270) 5-HT1B (6170) H3 (7300)	40 µM	in vitro	Male Sprague-Dawley rats	Picrotoxin (i.c. in hippocampal slices)	[155]
		1 µM	in vitro	Wistar rat embryos	High K⁺ (7 mM) in hippocampal and prefrontal cells	[156]
		100 µM	in vitro	Male Swiss mice	Mg²⁺-free model in olfactory bulb slices	[157]
		100 µM	in vitro	Male Wistar rat pups	Low Mg²⁺/high K⁺ in hippocampal slices	[158]
		100 µM	in vitro	Male Wistar rat pups	4-AP in hippocampal slices	[158]
		ED₅₀ = 8.2–15.9 mg/kg	i.p., 4 h; i.p., 28-day treatment, 4 h before the sound	Genetically epilepsy-prone rats (GEPR-9 s)	Sound	[159]
		3.5 and 7.0 nmol	i.c., 15 min	Male Sprague-Dawley rats	BIC (118 pmol, i.c.)	[160]
		20 mg/kg	i.p., 1 h	Male Sprague-Dawley rats	BIC (118 pmol, i.c.)	[161]
		15 mg/kg	i.p., 1 h	Genetically epilepsy-prone rats (GEPR-9 s)	Sound (115 dB)	[162], [163]
		10 mg/kg	i.p., 1 week after 21-day pretreatment	Male Wistar rats	Electrical hippocampal stimulation	[164]
		20 mg/kg	i.p. for five days (after)	Male Sprague-Dawley rats	Pilocarpine (320 mg/kg, i.p.)	[165]
		20 mg/kg	i.p., 65 min	Male CBA mice	Picrotoxin (0.75 mg/ml at a rate of 1.1 ml/min, i.v.)	[166]
		20 mg/kg	s.c., 60 min	Male CFLP mice	PTZ (130 mg/kg, s.c.)	[167]
		10 mg/kg/day	7 days	El mice	Handling-induced	[168]
		25 mg/kg	i.p., 2 h	Genetically epilepsy-prone rats (GEPR-9 s)	Sound (100 dB)	[169]
		20 mg/kg	i.p.	Groggy (GRY/Idr) rats	Absence-like seizures	[170]
		30 mg/kg/day	i.p. for 17 weeks	WAG/Rij rats	Absence-like seizures	[171]
		10 mg/kg	i.p. for 7 days (after)	Male rats	4-AP (3 mg/kg, i.p.)	[172]
		5 and 10 mg/kg	i.p., 30 min	Male Wistar rats	Penicillin (500 IU/2.5 µl, i.c.)	[173]
		10 mg/kg	i.p., 30–60 min	Male and female C57BL/6J mice	Amygdala-kindling	[122]
		20 mg/kg	p.o.	Seizure-susceptible Wistar rats	Sound (90–110 dB)	[174]
		10 mg/kg	i.p., 30 min	Male Wistar rats	PTZ (45 mg/kg, i.p.)	[175]
Fluvoxamine K_i= 36	SERT (2–540) DAT (2–9200) NET (299–5000) Alpha1 (1290–4800) Alpha2 (1900) K⁺ channels (IC₅₀ = 3100) Ca²⁺ channels (IC₅₀ = 4900) 5-HT2C (5790–6700) TMEM97 (8439)	20 mg/kg	i.p., 30 min	Male mice	PTZ-induced kindling (35 mg/kg, i.p.)	[176]
Ifenprodil (erythro diastereomer) K_i= 2–125	TMEM97 (5–98) EBP (1.0) 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)	IC₅₀ = 6.3 µM	in vitro	Male Wistar rats	Mg²⁺-free model in hippocampal slices	[104]
		3 µM	in vitro	Sprague-Dawley rats	BIC (10 µM) in hippocampal slice cultures	[177]
		10 µM	in vitro	Human	Mg²⁺-free model in slices from dysplastic human neocortex	[178]
		10 mg/kg	i.v., 30 min	Male To mice	NMDLA (85 mg/ml at a rate of 0.14 ml/min, i.v.)	[179]
		ED₅₀ = 61 mg/kg	i.p., 30 min	Male NSA/CF1 mice	MES (auricular)	[107]
		60 mg/kg	i.p., 30 min	Male NSA/CF1 mice	NMDA (250 mg/kg, i.p.)	[107]
		ED₅₀ = 40 mg/kg	i.p.	Male OF-1 mice	Handling-induced and strychnine- potentiated convulsions	[180]
		ED₅₀ (clonus) = 1.1 µmol/kg	i.p., 60 min	Genetically epilepsy-prone rats (GEPR-9 s)	Sound (109 dB)	[138]
		50 pmol	i.c.	Male Wistar rats	Putrescine (10–20 nmol, i.c.)	[181]
		20 mg/kg	i.p., 30 min	ddY mice	PTZ (100 mg/kg, s.c.)	[182]
		100 µg	i.c.v.	Male Sprague-Dawley rats	Amygdala-kindling	[183]
		30 mg/kg	i.p.	Male Sprague-Dawley rats	Status epilepticus	[184]
		20, 40 and 60 mg/kg	i.p., 60 min	Male Wistar rats	PTZ (100 mg/kg, s.c.)	[185]
		ED₅₀ = 15.5 mg/kg	i.p., 30 min	Male Wistar rats	Lindane (8 mg/kg, i.p.)	[186]
		20 mg/kg	i.p.	Male Wistar rats	Electrical stimulation-induced cortical epileptic afterdischarges	[187]
		20 mg/kg	i.p. for one-two weeks every 8 h during epileptogenesis	C57BL/6J mice	Kainic acid (20 mM, i.c.)	[188]
Opipramol K_i= 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)	IC₅₀ = 52 µM	in vitro	Male Wistar rats	Mg²⁺-free model in hippocampal slices	[104]
Opipramol K_i= 0.2–50.0		20 mg/kg	i.p., 30 min	Male Swiss mice	PTZ (100 mg/kg, i.p.)	[189]
( ± )Pentazocine K_i= 15–135	Kappa opioid R (2–75) Mu opioid R (3–7) NMDAR (25–2820) Delta opioid R (49) TMEM97 (1500–1900) D2 (3500)	ED₅₀ = 7.9–11.6 µM	in vitro	Wistar rats	NMDA (10–80 µM) in neocortical slices	[87]
		4, 8 and 16 mg/kg	s.c., 30 min	Male NMRI mice	MES (corneal)	[190]
		ED₅₀ = 6 mg/kg	s.c.	Male NMRI mice	PTZ (1% at a rate of 0.3 ml/min, i.v.)	[190]
		10–160 µg	i.c.v.	Male Sprague-Dawley rats	Flurothyl	[191]
		ED₅₀ = 63.3 mg/kg	s.c., 30 min	Male Swiss-Webster mice	NMDLA (500 mg/kg, s.c.)	[192]
		10–50 mg/kg	i.p.	Mice	MES	[193]
Sig1R antagonists* *
*BD-1063 K_i= 6–9 nM	TMEM97 (210–318)	* 3 nmol	i.c.v.	Male CD-1 mice	NMDA (1 nmol, i.c.v.)	[39]
* ( ± )Fenfluramine (ZX008) K_i= 266	SERT (108) 5-HT1A (327) 5-HT2B (400–5710) NET (740–1990) 5-HT2C (1410–3183) 5-HT2A (3800–5460) Na⁺ channels (4840)	500 µM	in vitro	Wistar rats	Low Mg²⁺ model in brain slices	[194]
		50 μM	in vitro, 24 h before recordings	Mutant Scn1Lab^-/- zebrafish larvae	Spontaneous seizures	[195]
		* 25 µM	in vitro	Mutant Scn1Lab^-/- zebrafish larvae	Spontaneous seizures	[196], [197]
		20 mg/kg	i.p., 45 min	Male CD-1 mice	MES-T	[198]
* (+)Fenfluramine IC₅₀= 70	SERT (150–855) NET (1286) 5-HT2C (362–6245) 5-HT2B (379–5099) 5-HT2A (2470–11107)	* 3 nmol	i.c.v.	Male CD-1 mice	NMDA (300 pmol, i.c.v.)	[199]
* (+)Fenfluramine IC₅₀= 70		100 µM	in vitro	Mutant Scn1Lab^-/- zebrafish larvae	Spontaneous seizures	[200]
*S1RA (E-52862, MR-309) K_i= 3–24 nM	5-HT2B (328) TMEM97 (9300)	* 3 nmol	i.c.v.	Male CD-1 mice	NMDA (300 pmol, i.c.v.)	[199]
(S)Safinamide (FCE 26743, NW 1015, PNU 151774, PNU 151774E) IC₅₀= 19	MAO-B (2–450) TMEM97 (1590)	ED₅₀ = 4.1 mg/kg (i.p.); ED₅₀ = 6.9 mg/kg (p.o.)	i.p.; p.o.	Mice	MES	[201], [202]
		ED₅₀ = 8.0 mg/kg (i.p.); ED₅₀ = 11.8 mg/kg (p.o.)	i.p.; p.o.	Rats	MES	[201], [202]
		ED₅₀ = 26.9 mg/kg	p.o.	Mice	BIC	[201]
		ED₅₀ = 60.6 mg/kg	p.o.	Mice	Picrotoxin	[201]
		ED₅₀ = 21.5 mg/kg	p.o.	Mice	3-MPA	[201]
		ED₅₀ = 26.8 mg/kg	p.o.	Mice	PTZ	[201]
		ED₅₀ = 104.1 mg/kg	p.o.	Mice	Strychnine	[201]
		10 and 30 mg/kg	i.p., 15 min	Male Wistar rats	Kainic acid (10 mg/kg, i.p.)	[203]
		10 and 30 mg/kg	i.p., 60 min	Male Wistar rats	Amygdala-kindling	[204]
		50 mg/kg (p.o.)	p.o.	Male cynomologus monkeys	Electrically induced afterdischarges	[205]
		ED₅₀ = 4.1 mg/kg	i.p.	Male Carworth Farms No. 1 mice	MES	[206]
		ED₅₀ = 12 mg/kg	p.o.	Sprague-Dawley rats	MES	[206]
Sertraline (1S-cis isomer) K_i= 29–57	SERT (0.1–3.4) DAT (25–260) Alpha1 (36–335) Alpha2 (83–651) NET (159–978) M1 (310–430) M5 (365) M4 (367) 5-HT2C (567–2300) 5-HT2A (783–2200) M2 (984) Ca²⁺ channels (1305–2084) 5-HT2B (2160) Na⁺ channels (2334) MC5 (4313) 5-HT1A (3700) H1 (5000–6600) TMEM97 (5297) K⁺ channels (6814)	15 and 30 mg/kg	i.p., 8 h	Genetically epilepsy-prone rats (GEPR-9 s)	Sound (115 dB)	[207]
		25 mg/kg	i.p., 4 h	Male Wistar rats	4-AP (2.5 mg/kg, i.p.)	[208], [209]
		2.5 and 25 mg/kg	i.p., 4 h	Male Wistar rats	PTZ (50 mg/kg, i.p.)	[208]
Positive allosteric modulators of Sig1R
*E1R (4 R,5S-methylphenylpiracetam)	N/A	* 10 and 50 mg/kg	i.p., 60 min	Male Swiss-Webster mice	PTZ (1% at a rate of 0.6 ml/min, i.v.)	[210]
		50 mg/kg	i.p., 60 min	Male Swiss-Webster mice	BIC (0.01% at a rate of 0.6 ml/min, i.v.)	[210]
		75 mg/kg	i.p., 30 min	Male Swiss-Webster mice	NE-100 (75 mg/kg, i.p.)	[210]
*SKF-83959	D1 (1–8) 5-HT2A (266) Alpha2 (295) D3 (399) D2 (920)	* 10, 20 and 40 mg/kg	i.p., 40 min	Male C57BL/6J mice	MES-T	[93]
		* 20 and 40 mg/kg	i.p., 40 min	Male C57BL/6J mice	PTZ (80 mg/kg, s.c.)	[93]
		* 40 mg/kg	i.p., 40 min	Male C57BL/6J mice	Kainic acid (30 mg/kg, i.p.)	[93]
*SOMCL-668	N/A	* 40 mg/kg	i.p., 40 min	Male C57BL/6J mice	MES-T	[93]
		* 40 mg/kg	i.p., 40 min	Male C57BL/6J mice	PTZ (80 mg/kg, s.c.)	[93]
		* 40 mg/kg	i.p., 40 min	Male C57BL/6J mice	Kainic acid (30 mg/kg, i.p.)	[93]
Ropizine (SC-13504)	N/A	4–8 mg/kg	i.v.	Papio papio baboons	Photosensitive epilepsy	[211]
		3–6 mg/kg	-	Beagle dogs	MES	[212]
		3, 30 and 300 mg/kg	p.o., 30 min	Male Sprague-Dawley rats	Pre-kindled and partially kindled hippocampal seizures	[213]

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 (K_i) to targets of compounds at concentrations below 10 µM (< 1 ×10^-5). Bolded targets – equal or higher affinity than for Sig1R. N/A – not available. 3-MPA – 3-mercaptopropionic acid; 4-AP – 4-aminopyridine; AMPA – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BIC – bicuculline; MES – maximal electroshock-induced seizures; MES-T – maximal electroshock seizure threshold; NMDA – N-methyl-D-aspartic acid; NMDLA – N-methyl-DL-aspartic acid; PIC – picrotoxin; PTZ – pentylenetetrazole; STRYC – strychnine. Targets: 5-HT1-7 – serotonin receptor subtypes; alpha-1 and alpha-2: adrenergic receptors; AchE – acethylcholine esterase; DAT – dopamine transporter; EBP – emopamil binding protein; ERG2 – C8 sterol isomerase; MAO-B – monoamine oxidase B; Mu, Kappa, Delta – opioid receptor subtypes; nAChRs – nicotinic actehylcholine receptors; Na⁺, K⁺ and Ca²⁺ - corresponding ion channels; NET – norepinephrine transporter; NMDAR – N-methyl-D-aspartate receptors; NOP R – nociceptin opioid peptide receptor; SERT – serotonin transporter; TMEM97 – transmembrane protein 97; VAChT – vesicular acethylcholine transporter. *Sig1R-dependent activity confirmed. * *Sig1R antagonists demonstrate anti-seizure activity against seizures induced by psychostimulants and drugs of abuse (for more details see Section 3.1.2.).