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)

In the isolated basal hippocampal formation, the proconvulsant effects of dopamine (10 μM) are totally eliminated by ecopipam (2 μM) hydrochloride [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 hydrochloride (0.003-0.3 mg/kg; single dosage; subcutaneous injection) removes the potentiating effects of island nicotine inducers as sensory enhancers [3]. Ecopipam Hydrochloride (10 mg/kg, Intermediate) Overlapping Antioxidants in Apomorphine-Induced Stereotypy Ecopipam Hydrochloride (5 and 10 μM, perfusion, 1 μL/min) reversibly and dose-dependently decreases striatal apomorphine Release of choline [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 youth Long-Evans impression [4]. Nicotine injected rats [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: Pressure on active and inactive levers diminished in a dose-dependent manner.

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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.

Drug Indication
Treatment of Tourette syndrome

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To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 μM) attenuated epileptiform activity, whereas >3 μM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 μM) or the D2-like antagonist sulpiride (10 μM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect. [2]

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Rationale and objectives: The reinforcement-enhancing effect (REE) of nicotine refers to the drug's ability to enhance the strength of other primary and conditioned reinforcers. The main aim was to investigate neuropharmacological mechanisms underlying nicotine's strengthening of a primary visual reinforcer (i.e., a light cue), using a subcutaneous (SC) dose previously shown to provide plasma nicotine levels associated with habitual smoking. Methods: 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). Results: The nicotine REE was abolished by three antagonists at doses that did not impact motor output, i.e., mecamylamine (1 mg/kg), SCH 39166 (0.01 and 0.03 mg/kg), and naloxone (5 mg/kg). Prazosin and rimonabant both attenuated the nicotine REE, but rimonabant also suppressed responding more generally. The nicotine REE was not significantly altered by sulpiride or propranolol. Conclusions: In adult male rats, the reinforcement-enhancing effect of low-dose nicotine depends on nicotinic receptor stimulation and on neurotransmission via D1/D5 dopaminergic, opioid, alpha1-adrenergic, and CB1 cannabinoid receptors. [3]

C19H20NOCL.HCL

350.28214

349.1

C, 65.15; H, 6.04; Cl, 20.24; N, 4.00; O, 4.57

190133-94-9

Ecopipam hydrobromide;2587360-22-1;Ecopipam;112108-01-7

170317

White to off-white solid powder

4.72

2

2

0

23

403

2

CN1CCC2=CC(=C(C=C2[C@@H]3[C@@H]1CCC4=CC=CC=C34)O)Cl.Cl

APFMVAHRFWBCDG-JUOYHRLASA-N

InChI=1S/C19H20ClNO.ClH/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;1H/t17-,19+;/m0./s1

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

Ecopipam hydrochloride; 190133-94-9; Ecopipam HCl; Sch 39166; Ecopipam hydrochloride [USAN];

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~100 mg/mL (~285.49 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.14 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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