Igmesine
Igmesine (JO 1784) is a selective σ-1 receptor agonist (IC50 = 39 nM) with oral activity and blood-brain barrier penetration. Igmesine stimulates duodenal bicarbonate secretion in rats via a σ1/vagal/CCK-A-dependent pathway, without antisecretory activity. Igmesine centrally blocks CRF-mediated gastrin-inhibitory effects, and in TMT toxicity and MCAO focal ischemia models, it downregulates PTBBS, reduces NOS, and modulates M1/M2 density. Igmesine is used in research on duodenal ulcers, Alzheimer's disease, and related diseases.
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- No. CAS: 140850-73-3
- Fòrmula: C23H29N
- Peso molecular:319.49
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Almacenamiento:
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Actividad biológica
Descripciòn
IC50 & Target
[1]|
σ1 39 nM (IC50) |
In Vitro
Igmesine is a highly selective σ receptor ligand with strong in vitro binding affinity for σ sites, whereas its enantiomer JO 1783 shows negligible σ receptor binding activity[2].
Igmesine binds potently and selectively to σ sites in rat brain membrane preparations with an IC50 of 39 nM; it shows extremely low affinity for the phencyclidine binding site of the NMDA receptor and exhibits no significant affinity for the other 23 receptor sites tested[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
Igmesine (0.03 μg; microinjected into the paraventricular nucleus (PVN) or lateral hypothalamus (LH); single dose; 10 min before microinjection of corticotropin-releasing factor (CRF) into the same nucleus) microinjected into the PVN completely blocks the inhibitory effect of CRF on pentagastrin-stimulated gastric acid secretion, whereas microinjection into the LH has no such effect[1].
Igmesine (1-10 mg/kg; p.o.; administered orally 1 h before cysteamine; single dose) potently protects rats against cysteamine-induced duodenal ulcers with an oral ED50 of 4.14 mg/kg, and this activity is blocked by σ receptor antagonists and peripheral cholecystokinin A receptor antagonists[2].
Igmesine (p.o.) mildly protects rat gastric mucosa from injury, with oral ED50 values ranging from 25.2 to 55.4 mg/kg depending on the ulcerogenic stimulus[2].
Igmesine (1-30 mg/kg; intradermal injection; single dose) does not inhibit gastric acid secretion in pylorus-ligated rats at high doses[2].
Igmesine (0.25-2 mg/kg; intravenous injection; single bolus) stimulates duodenal bicarbonate secretion in Rattus norvegicus in vivo in a dose-dependent manner, and this activity is mediated by σ receptors, vagal pathways, and peripheral cholecystokinin A receptors[2].
Igmesine (1.2-3.5 mg/kg; i.p., p.o.; single dose; 30 min before radiotracer injection) is a highly potent, selective, and well-tolerated σ-site ligand in mice, with ID50 values for in vivo displacement of (+)-[3H]SKF 10,047 binding to σ sites of 1.2 mg/kg for i.p. administration and 3.5 mg/kg for p.o. administration[4].
Igmesine (1-16 mg/kg; i.p.; once daily; for 40 days) exerts neuroprotective effects against trimethyltin-induced muscarinic receptor loss in male Sprague-Dawley rats, attenuating the reduction in M1 and M2 receptor density in multiple brain regions, with the most pronounced effects in the cortex, hippocampus, amygdala, and hypothalamus[6].
Igmesine (1-16 mg/kg; i.p.; once daily; for 40 days) decreases M1 and M2 muscarinic receptor density in multiple brain regions of healthy male Sprague-Dawley rats[6].
Igmesine (0.03 mg/kg i.p.; once daily; for 7 consecutive days) acts synergistically with FENM to alleviate Aβ25-35-induced learning impairment in mice in both short-term and long-term memory tests[3].
Igmesine (2.5-10 mg/kg; i.p.; multiple injections at 5-45 min and 3-54 h after occlusion) exerts neuroprotective effects in a mouse model of focal cerebral ischemia, and at all tested doses, it significantly inhibits ischemia-induced increases in ω3 site density and significantly suppresses ischemia-induced increases in NOS activity[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague-Dawley albino (male, 250-350 g, fasted 18 h before study, anaesthetized with urethane)[1]
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Dosage:0.01 μg; 0.1 μg; 0.5 μg
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Administration:i.c.; single dose; 10 minutes prior to intracisternal injection of CRF, bombesin, or hIL-1β
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Result:Did not modify pentagastrin-stimulated gastric acid secretion.
Dose-dependently prevented CRF-induced 72% inhibition of pentagastrin-stimulated gastric acid secretion.
Completely abolished the CRF effect at the 0.5 μg dose.
Did not alter the 56% inhibition induced by bombesin or the 62% inhibition induced by hIL-1β at the 0.5 μg dose.
Lost the ability to block CRF-induced inhibition of gastric acid secretion when rats were pretreated subcutaneously with BMY 14802.
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Animal Model:Sprague-Dawley albino (male, 250-350 g, fasted 18 h before study, anaesthetized with urethane, guide cannulae implanted 7 days prior using dissociative anaesthetic/sedative analgesic anaesthesia)[1]
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Dosage:0.03 μg
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Administration:microinjection into PVN or LH; single dose; 10 minutes prior to microinjection of CRF into the same nucleus
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Result:Did not modify pentagastrin-stimulated gastric acid secretion when microinjected into the PVN.
Completely prevented the 61% inhibition of pentagastrin-stimulated gastric acid secretion induced by CRF microinjected into the PVN, with gastric acid output reaching 184 μmol/90 min compared to 76 μmol/90 min in the CRF-only group.
Did not alter the 51% inhibition of pentagastrin-stimulated gastric acid secretion induced by CRF microinjected into the LH when microinjected into the LH.
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Animal Model:Sprague-Dawley (male, 180-220 g, cysteamine-induced duodenal ulcers)[2]
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Dosage:1-10 mg/kg
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Administration:p.o.; single dose 1 hour before cysteamine
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Result:Induced 15% inhibition of the ulcer index.
Induced 48% inhibition of the ulcer index.
Induced 71% inhibition of the ulcer index, reducing mean ulcer index from 33.2 mm2 to 9.7 mm2.
Exhibited an ED50 of 4.14 mg/kg p.o. for ulcer protection.
Lost ulceroprotective effect when pretreated with haloperidol, BMY 14,802, or devazepide.
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Animal Model:Sprague-Dawley (male, 250-400 g, pylorus-ligated Shay rat preparation)[2]
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Dosage:1-30 mg/kg
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Administration:i.d.; single dose immediately after pylorus ligation
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Result:Did not significantly modify gastric acid volume, free acid concentration or output, or total acid concentration or output at any tested dose.
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Animal Model:Sprague-Dawley (male, 250-400 g, in situ cannulated duodenum preparation under Inactin anesthesia)[2]
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Dosage:0.25 mg/kg; 0.5 mg/kg; 1 mg/kg; 2 mg/kg
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Administration:i.v.; single bolus
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Result:Induced a dose-dependent increase in duodenal bicarbonate output, with a threshold dose of 0.25 mg/kg i.v.
Increased bicarbonate output from a basal 7.60 μEq·cm-1·h-1 to a plateau of 14.8 μEq·cm-1·h-1 at 1 mg/kg i.v., which persisted for 2 hours.
Did not further increase bicarbonate secretion at 2 mg/kg i.v.
Lost stimulatory effect when pretreated with bilateral vagotomy, tetrodotoxin, hexamethonium, haloperidol, BMY 14,802, or devazepide.
Retained stimulatory effect when pretreated with atropine, SCH 23,390, sulpiride, prazosin, yohimbine, naloxone, or indomethacin.
Retained stimulatory effect after intracerebroventricular administration of devazepide.
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Animal Model:Swiss OF-1 (male, 7-9 weeks old, weight 32 g)[3]
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Dosage:0.03 mg/kg; 0.1 mg/kg; 0.3 mg/kg; 0.03 mg/kg (combined with 0.01 mg/kg FENM)
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Administration:i.p.; daily; 7 days
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Result:Prevented Aβ25-35-induced spontaneous alternation deficits.
Showed less effectiveness on passive avoidance deficits.
Produced synergistic protection (combination index < 1) in both Y-maze spontaneous alternation test and passive avoidance test when combined with 0.01 mg/kg FENM.
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Animal Model:Swiss mice (male, 20-22 g)[4]
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Dosage:1.2 mg/kg (i.p.); 3.5 mg/kg (p.o.); up to 600 mg/kg (p.o., toxicity); >1000 mg/kg (p.o., LD50)
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Administration:i.p.; single dose; 30 minutes prior to radiotracer injection; p.o.; single dose; 30 minutes prior to radiotracer injection
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Result:Displaced (+)-[3H]SKF 10,047 from brain σ-sites with an ID50 of 1.2 mg/kg (i.p.).
Displaced (+)-[3H]SKF 10,047 from brain σ-sites with an ID50 of 3.5 mg/kg (p.o.).
Inhibited σ-site binding by at least 60% four hours after i.p. administration.
Inhibited σ-site binding by 30% four hours after p.o. administration.
Showed no toxic effects at oral doses up to 600 mg/kg.
Had an LD50 > 1000 mg/kg orally.
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Animal Model:Swiss mice (4-week-old male, 20-25 g, OF-1 Iffa Credo, France)[5]
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Dosage:2.5 mg/kg; 5.0 mg/kg; 10.0 mg/kg
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Administration:i.p.; multiple doses at 5, 15, 45 min and 3, 6, 18, 24, 36, 48, 54 h post-occlusion
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Result:Reduced ipsilateral cortical ω3 site densities to 74.89 pmol/mg protein at 2.5 mg/kg, 126.22 pmol/mg protein at 5.0 mg/kg, and 116.16 pmol/mg protein at 10.0 mg/kg.
Caused no changes in contralateral cortical ω3 site densities at any dose.
Reduced cerebellar NOS activity to 0.1622 pmol/μg protein/h and brain-stem NOS activity to 0.1502 pmol/μg protein/h at 2.5 mg/kg.
Reduced cerebellar NOS activity to 0.2168 pmol/μg protein/h and brain-stem NOS activity to 0.0894 pmol/μg protein/h at 5.0 mg/kg.
Reduced cerebellar NOS activity to 0.1280 pmol/μg protein/h and brain-stem NOS activity to 0.0914 pmol/μg protein/h at 10.0 mg/kg.
Reduced infarct volume to 16.355 mm3 at 2.5 mg/kg, 13.484 mm3 at 5.0 mg/kg, and 16.320 mm3 at 10.0 mg/kg.
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Animal Model:Sprague-Dawley (male, mean body weight 280-320 g, neurotoxicity model via single i.p. injection of trimethyltin chloride)[6]
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Dosage:1 mg/kg; 4 mg/kg; 16 mg/kg
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Administration:i.p.; daily; 40 days
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Result:Produced significant increases in M1 receptor density in the cortex, olfactory regions, septum, thalamus, and basal forebrain nuclei.
Prevented 65-67% of trimethyltin-induced M1 receptor loss in the septum at 1 and 4 mg/kg, and 22% at 16 mg/kg, with additional protection in the substantia innominata and ventral pallidum across all doses.
Caused a small 1-3% decrease in M1 receptor density in the hippocampal CA2 and CA3 regions.
Attenuated trimethyltin-induced M2 receptor loss with significant increases in the amygdaloid nuclei (5-12% increase), basal ganglia (5-8% increase), frontal-parietal motor cortex layers III-IV (17-27% increase), hippocampal CA1 (9-10% increase), CA2 (13-16% increase), CA3 (11-12% increase), and hypothalamus (22-31% increase).
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Animal Model:Sprague-Dawley (male, mean body weight 280-320 g)[6]
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Dosage:1 mg/kg; 4 mg/kg; 16 mg/kg
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Administration:i.p.; daily; 40 days
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Result:Decreased M1 receptor density in the amygdaloid nuclei, basal ganglia, cortex, and hippocampus, with the greatest decrease (33%) in the hippocampal CA1 field at 1 mg/kg, and a 17% decrease in the nucleus accumbens at 1 mg/kg.
Decreased M2 receptor density in the amygdaloid nuclei, basal ganglia, cortex, hippocampus, hypothalamus, and septal regions, with significant reductions observed across multiple subregions of these areas at various doses.
Chemical Information
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No. CAS 140850-73-3
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Peso molecular 319.49
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Fòrmula C23H29N
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SMILES
C(N(CC1CC1)C)(C/C=C/C2=CC=CC=C2)(CC)C3=CC=CC=C3
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Synonyms
JO 1784
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[2]. Pascaud XB, et al. Effects of a new sigma ligand, JO 1784, on cysteamine ulcers and duodenal alkaline secretion in rats. Gastroenterology. 1993 Feb;104(2):427-34. [Content Brief]
[4]. Roman FJ, et al. JO 1784, a potent and selective ligand for rat and mouse brain sigma-sites. The Journal of pharmacy and pharmacology. 1990 Jun;42(6):439-40. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Igmesine Related Classifications
HY-169914A Related Classifications
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