D1 Receptor (Ki = 1.2 nM); D5 Receptor (Ki = 2.0 nM); D2 Receptor (Ki = 980 nM); D4 Receptor (Ki = 5520 nM); 5-HT Receptor (Ki = 80 nM); Alpha-2A adrenergic receptor (Ki = 731 nM)

The proconvulsant effects of dopamine (10 μM) in the hippocampus formation are entirely eliminated from the body by ecopipam (2 μM) [2]. Researchers tested the effect of SCH39166, an antagonist of D1-like receptors, on low-Mg2+-induced epileptiform activity. Application of 2 μM SCH39166 itself had no significant effect on the properties of SLE or non-SLE, but SCH39166 prevented the proconvulsive effect of dopamine. In the presence of 2 μM SCH39166, bath application of 10 μM dopamine did not enhance the power of epileptiform activity, and the dopamine-induced increase in the occurrence of non-SLE (Fig. 5A,F) and the number of spikes per non-SLE event was abolished. In addition, the anticonvulsive effect of 0.1 μM dopamine was also completely blocked in the presence of 2 μM SCH39166 [2].

Ecopipam (0.003-0.3 mg/kg; single dose; subcutaneous injection) eliminates the potentiating effects of prostate nicotine induction [3]. Ecopipam (5 and 10 μM, perfusion, 1 μL/min) reversibly and dosewise reduces cholinergic release in the striatum [5].

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In vivo, SCH39166 inhibited both rat and squirrel monkey conditioned avoidance responding (minimal effective dose = 10 and 1.78 mg/kg p.o., respectively) and had a duration of at least 6 hr in both species. In addition, SCH39166 antagonized apomorphine-induced stereotypy in rats (minimal effective dose = 10 mg/kg p.o.). These in vivo actions of SCH39166 are similar to the activity of typical dopamine antagonists. However, in contrast to D2-selective antagonists, SCH39166 failed to increase plasma prolactin levels, did not block apomorphine-induced emesis in the dog and had minimal effects on the striatal levels of homovanillic acid or dihydroxyphenylacetic acid. Furthermore, although immobility was seen after p.o. administration of SCH39166 using the inclined screen test, the drug did not cause catalepsy at doses up to 10 times its minimal effective dose in the rat conditioned avoidance response test. Additionally, SCH39166 inhibited apomorphine-induced climbing at lower doses than it inhibited apomorphine-induced sniffing in mice. The results from these latter two tests suggest that SCH39166 may have a reduced liability to produce extrapyramidal side effects. Therefore, based on this profile of activity, SCH39166 is a selective D1 dopamine receptor antagonist both in vitro and in vivo. Additionally, because this compound is longer acting in the primate than previously available D1 antagonists, it has potential utility as a clinically useful drug. [4]

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The effect of local application by reverse dialysis of the dopamine D(1) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride (SCH 39166) on acetylcholine release was studied in awake, freely moving rats implanted with concentric microdialysis probes in the dorsal striatum. In these experiments, the reversible acetylcholine esterase inhibitor, neostigmine, was added to the perfusion solution at two different concentrations, 0.01 and 0.1 microM. SCH 39166 (1, 5 and 10 microM), in the presence of 0.01 microM neostigmine, reversibly decreased striatal acetylcholine release (1 microM SCH 39166 by 8+/-4%; 5 microM SCH 39166 by 24+/-5%; 10 microM SCH 39166 by 27+/-7%, from basal). Similarly, SCH 39166, applied in the presence of a higher neostigmine concentration (0.1 microM), decreased striatal acetylcholine release by 14+/-4% at 1 microM, by 28+/-8% at 5 microM and by 30+/-5% at 10 microM, in a dose-dependent and time-dependent manner. These results are consistent with the existence of a facilitatory tone of dopamine on striatal acetylcholine transmission mediated by dopamine D(1) receptors located on striatal cholinergic interneurons. [5]

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Rats' apomorphine-induced stereotypy is countered by ecopipam hydrobromide (10 mg/kg, oral)[4]. Acetylcholine release in the rat striatum is reversibly and dose-dependently reduced by ecopipam hydrobromide (5 and 10 μM, perfusion, 1 μL/min)[5].

Dopamine hydrochloride was added at 0.1, 0.3, 1, 3, 10, and 30 μM in the continuous presence of 5 μM nomifensine (1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinamin maleate) and 100 μM sodium metabisulfide to prevent endogenous dopamine reuptake and oxidation of dopamine. Dopamine receptors were activated by the subtype-specific agonists (±)-SKF-38393, GSK 789472 hydrochloride, and (−)-quinpirole hydrochloride. The following dopamine receptor antagonists were used: (R)-(+)-SCH-39166 hydrochloride (Sigma), L-741626 (3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole), (−)-sulpiride, and SB-277011A. In some experiments, adrenergic receptors were blocked by the combined application of (RS)-propranolol hydrochloride and phentolamine mesylate. GABAA and NMDA receptors were blocked by using gabazine (SR-95531) and DL-2-amino-5-phosphonopentanoic acid (±-APV), respectively. AMPA receptors were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or GYKI 52466 (4-(8-methyl-9H-1,3-dioxolo[4,5-][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride). Dopamine was prepared freshly in sodium metabisulfite containing ACSF every day. (±)-APV, GSK 789472, propranolol, and phentolamine were used from an aqueous stock solution and all other agonists and antagonists from a stock solution in dimethylsulfoxide (DMSO). The DMSO concentration in the bathing solution never exceeded 0.1%. [2]

Animal/Disease Models: Male young adult Long-Evans rats were injected with nicotine [3]
Doses: 0.003, 0.01, 0.03, 0.1, 0.3 mg/kg
Route of Administration: Single subcutaneous injection 20 minutes before nicotine (0.1 mg/kg)
Experimental Results: Dose-dependent reduction of pressure on active and inactive levers.

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Adult male rats pressed an “active” lever to illuminate a brief cue light during daily 60-min sessions. Rats that showed a clear REE were tested with systemically administered pretreatment drugs followed by nicotine (0.1 mg/kg SC) or saline challenge, in within-subject counterbalanced designs. Pretreatments were mecamylamine (nicotinic, 0.1-1 mg/kg SC), SCH 39166 (D1-like dopaminergic, 0.003-0.2 mg/kg SC), naloxone (opioid, 1 and 5 mg/kg SC), prazosin (alpha1-adrenergic antagonist, 1 and 2 mg/kg IP), rimonabant (CB1 cannabinoid inverse agonist, 3 mg/kg IP), sulpiride (D2-like dopaminergic antagonist, 40 mg/kg SC), or propranolol (beta-adrenergic antagonist, 10 mg/kg IP).[3]

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Experiment 3: SCH 39166 dose-response [3]
Experiment 3.1 Here, lower doses of SCH 39166 were tested for selective inhibition of the nicotine REE. Subjects comprised the 32 rats that had completed Experiment 1 with the highest response rates. Before antagonist/nicotine testing, performance was verified by giving each rat two drug-free sessions, followed by one test each with either saline or nicotine (counterbalanced order); as a result, one rat was removed. The subsequent drug testing block (n = 31) followed a 4 × 2 design (i.e., 8 sessions/rat): pretreatment with SCH 39166 (0, 0.01, 0.03, and 0.1 mg/kg SC), in combination with saline and nicotine challenge.
Experiment 3.2 Here, SCH 39166 was tested in an even lower dose range. Subjects (n = 32) were first tested on 5 drug-free days and then alternately with saline and nicotine 0.1 mg/kg SC for 12 days. A total of 23 rats were then tested in a 5 × 2 design (10 sessions/rat): pretreatment with saline (tested twice), and SCH 39166 (0.003, 0.01, and 0.3 mg/kg SC), in combination with saline and nicotine challenge.

[1]. Dopamine D1/D5 receptor antagonists with improved pharmacokinetics: design, synthesis, and biological evaluation of phenol bioisosteric analogues of benzazepine D1/D5 antagonists. J Med Chem. 2005 Feb 10;48(3):680-93.

[2]. Dopaminergic modulation of low-Mg²⁺-induced epileptiform activity in the intact hippocampus of the newborn mouse in vitro. J Neurosci Res. 2012 Oct;90(10):2020-33.

[3]. Nicotine-induced enhancement of a sensory reinforcer in adult rats: antagonist pretreatment effects. Psychopharmacology (Berl). 2021 Feb;238(2):475-486.

[4]. Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity. J Pharmacol Exp Ther. 1988 Dec;247(3):1093-102.

[5]. Local application of SCH 39166 reversibly and dose-dependently decreases acetylcholine release in the rat striatum. Eur J Pharmacol. 1999 Nov 3;383(3):275-9.

(6aS,13bR)-11-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzozazepine-12-ol is a benzozazepine compound.
Ectopaine has been used in clinical trials to investigate the treatment of Tourette syndrome, Lesch-Niehan syndrome, pathological gambling, and self-harm.
See also: Ectopaine hydrochloride (note moved here).

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To investigate whether epileptiform activity in the immature brain is regulated by dopamine, we used field potential recordings of the CA3 region to examine the effects of dopaminergic agonists and antagonists in intact in vitro preparations of isolated cortical hippocampal structures from immature (days 3 and 4 postnatal) C57/Bl6 mice. Reducing the extracellular Mg²⁺ concentration to 0.2 mM induced epileptiform discharges. Experiments showed that low concentrations of dopamine (<0.3 μM) attenuated epileptiform activity, while concentrations >3 μM of dopamine enhanced it. The D1 receptor agonist SKF38393 (10 μM) had a strong proconvulsant effect, while the D2 receptor-like agonist quetiapine (10 μM) had a weaker anticonvulsant effect. The proconvulsant effect of 10 μM dopamine could be completely blocked by the D1 receptor-like antagonist SCH39166 (2 μM) or the D2 receptor-like antagonist sulpiride (10 μM), while the D2 receptor antagonist L-741626 (50 nM) and the D3 receptor antagonist SB-277011-A (0.1 μM) had no such effect. The anticonvulsant effect of 0.1 μM dopamine could be inhibited by D1-like, D2, or D3 receptor antagonists. When AMPA, NMDA, or GABA(A) receptors were blocked, the proconvulsant effect of 10 μM dopamine was still observed. In summary, these results indicate that: 1) dopamine can affect epileptiform activity in the early developmental stage; 2) dopamine can have a bidirectional effect on excitability; 3) D1-like receptors mediate the proconvulsant effect of high concentrations of dopamine, but the pharmacological mechanism of its anticonvulsant effect is unclear; 4) dopamine-induced changes in the GABAergic and glutamatergic systems may contribute to this effect. [2]

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Background and Objectives: The enhancement effect (REE) of nicotine refers to the ability of the drug to enhance the strength of other primary and conditioned reinforcers. The main objective of this study was to investigate the neuropharmacological mechanism of nicotine enhancement of primary visual reinforcers (i.e., light signals) using a subcutaneous (SC) dose that, as previously shown, can achieve plasma nicotine levels associated with habitual smoking. Methods: Adult male rats pressed the “activation” lever to light up a brief cue light during a 60-minute experiment each day. Rats exhibiting significant resting energy expenditure (REE) were tested using a systemic drug pretreatment followed by stimulation with nicotine (0.1 mg/kg subcutaneously) or saline. The experiment employed a subject homeostasis design. Pretreatment drugs included: mecaramine (nicotine analogue, 0.1–1 mg/kg subcutaneously), SCH 39166 (D1-like dopaminergic drug, 0.003–0.2 mg/kg subcutaneously), naloxone (opioid, 1 and 5 mg/kg subcutaneously), prazosin (α1-adrenergic antagonist, 1 and 2 mg/kg intraperitoneally), rimonaban (CB1 cannabinoid inverse agonist, 3 mg/kg intraperitoneally), sulpiride (D2-like dopaminergic antagonist, 40 mg/kg subcutaneously), or propranolol (β-adrenergic antagonist, 10 mg/kg intraperitoneally). Results: All three antagonists, namely mecaramine (1 mg/kg), SCH 39166 (0.01 and 0.03 mg/kg) and naloxone (5 mg/kg), eliminated nicotine resting energy expenditure (REE) at doses that did not affect motor output. Prazosin and rimonaban both attenuated nicotine REE, but rimonaban also more generally inhibited the response. Sulpiride or propranolol had no significant effect on nicotine REE. Conclusion: In adult male rats, the enhancing effect of low-dose nicotine depends on stimulation of nicotine receptors and neurotransmission via D1/D5 dopaminergic receptors, opioid receptors, α1-adrenergic receptors and CB1 cannabinoid receptors. [3]

C19H20NOCL.HCL

350.28214

313.123

C, 72.72; H, 6.42; Cl, 11.30; N, 4.46; O, 5.10

112108-01-7

Ecopipam hydrobromide;2587360-22-1;Ecopipam hydrochloride;190133-94-9;rel-Ecopipam hydrobromide;1227675-51-5;Ecopipam-d4

107930

Typically exists as solid at room temperature

3.918

1

2

0

22

403

2

Cl.ClC1C=C2C(C3C(N(CC2)C)CCC2=CC=CC=C32)=CC=1O

DMJWENQHWZZWDF-PKOBYXMFSA-N

InChI=1S/C19H20ClNO/c1-21-9-8-13-10-16(20)18(22)11-15(13)19-14-5-3-2-4-12(14)6-7-17(19)21/h2-5,10-11,17,19,22H,6-9H2,1H3/t17-,19+/m0/s1

(6aS,13bR)-11-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzazepin-12-ol

Sch39166; 112108-01-7; Sch 39166; Sch-39166; Ecopipam [INN]; Sch39166; DTXSID8043814; UNII-0X748O646K; Sch-39166; Ecopipam

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)