Dopamine D2/D3 receptor
The primary targets of (-)-quinpirole hydrochloride are dopamine D2 and D3 receptors. Dopamine receptors are G protein-coupled receptors that mediate the effects of the neurotransmitter dopamine in the central nervous system. D2-like receptors (D2, D3, D4) are coupled to Gi/o proteins and inhibit adenylyl cyclase activity, reducing cAMP production. (-)-Quinpirole hydrochloride has high affinity for the D2 receptor (Ki = 4.8 nM) and D3 receptor (Ki = approximately 24 nM), with moderate affinity for D4 (Ki = approximately 30 nM) and very low affinity for D1 receptors (Ki = 1900 nM). This selectivity makes it a valuable tool for studying D2-like receptor-mediated functions. The compound's high affinity for D2 receptors has made it useful for investigating the role of dopamine D2 receptors in various neurological and psychiatric conditions.

Although DA content is left brain biased in all groups, with saline controls showing a larger asymmetry than all drug-treated groups, Side and Group do not significantly interact. When examining each side independently, it becomes clear that chronic quinpirole treatment causes DA levels in the left brain structure to gradually drop, with the QQ rats showing a notable difference from the saline controls. Conversely, acute Quinpirole only causes a significant (increased) change in right cortical DA levels. Across groups, DOPAC levels are also found to be left brain biased. Nevertheless, no noteworthy Group or interaction effects are discovered. When compared to the QS group or saline controls, rats given acute quinpirole exhibit a specific increase in DA content and decrease in turnover ratio. When compared to the acute quinpirole group, the DOPAC levels of sensitized (QQ) rats are higher. All three of the DA function measures in the striatum also showed significant group differences (DA, F_3,33=6.27, P=0.0020; F_3,33=7.98, P=0.0004; turnover ratio, F_3,33=16.85, P<0.0001), as well as differences in DA function. In comparison to all other groups, the acute quinpirole rats exhibit a significant decrease in both DOPAC and turnover ratio. The turnover ratio increased in both chronic quinpirole groups compared to both chronic saline groups, while DOPAC levels in QQ rats are significantly higher than in any other group[1].

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In vitro, (-)-quinpirole hydrochloride demonstrates potent agonist activity at dopamine D2 and D3 receptors. It has high affinity for D2 (Ki = 4.8 nM), D3 (approximately 24 nM), and D4 (approximately 30 nM) receptors, with much lower affinity for D1 receptors (1900 nM). The compound's activity is typically characterized using receptor binding assays and functional assays such as GTPγS binding, cAMP accumulation inhibition, or β-arrestin recruitment. (-)-Quinpirole hydrochloride has been shown to inhibit locomotor activity, consistent with its agonist activity at D2-like receptors. Its high selectivity and potency make it a valuable tool for studying dopamine receptor pharmacology and for distinguishing D2-like from D1-like receptor-mediated effects.

There was a left-brain bias in DA content between groups, and although this asymmetry was greater in the saline control group than in all drug-treated groups, there was no significant interaction between side and group. When considering each side individually, it can be seen that in left brain structures, DA levels gradually decrease with long-term quinpirole treatment, with significant differences between QQ rats and saline controls. In contrast, acute quinpirole only significantly altered (increased) right cortical DA levels. It was found that there was also a left-brain bias in DOPAC levels between groups. However, no significant group or interaction effects were found. Rats receiving acute quinpirole showed a selective increase in DA content and a decrease in turnover rate relative to the saline control or QS groups. However, DOPAC levels were increased in sensitized (QQ) rats compared with the acute quinpirole group. In the striatum, all three measures of DA function also differed significantly between groups (DA, F3,33=6.27, P=0.0020; DOPAC, F3,33=7.98, P=0.0004; turnover rate, F3,33=16.85, P <0.0001). In acute quinpirole rats, DOPAC and turnover rates were significantly reduced relative to all other groups. In QQ rats, DOPAC levels were significantly higher than all other groups, while in terms of turnover rate, both chronic quinpirole groups increased compared with the two chronic saline groups [1].

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Quinpirole, (4 aR-trans)-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-5-propyl-1 H-pyrazolo [3, 4-g]quinoline, is a dopamine agonist selective for the D2 subtype of dopamine receptors. In rats, quinpirole at doses of 0.3 mg/kg i.p. and higher decreased hypothalamic epinephrine concentrations. The doses required for this effect are only slightly higher than the minimum doses that decreased the concentration of dopamine metabolites in cerebral hemispheres. At higher doses of quinpirole (2-3 mg/kg i.p.), dopamine concentration was increased and norepinephrine concentration was decreased in hypothalamus, and MHPG sulfate (the norepinephrine metabolite) concentration was increased in brain stem and in hypothalamus. All of these neurochemical effects of quinpirole were blocked by pretreatment with spiperone, a dopamine antagonist. The effects were not produced by SKF 38393, a selective D1 agonist, or by the dextrorotatory enantiomer of quinpirole, which lacks D2 agonist activity. The data support the interpretation that quinpirole, by activating D2 receptors, results in a decrease in dopamine metabolites, a decrease in hypothalamic epinephrine concentration, and an increased conversion of norepinephrine to MHPG sulfate in rat brain probably through enhanced norepinephrine release[2].

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In vivo, (-)-quinpirole hydrochloride has been shown to inhibit locomotor activity, consistent with its agonist activity at D2-like dopamine receptors. This effect is characteristic of dopamine D2 receptor agonists, which can reduce motor activity at certain doses by activating presynaptic autoreceptors or postsynaptic receptors. The compound has been used extensively in behavioral pharmacology to study the role of dopamine D2 receptors in motor function, reward, and cognition. Its selectivity for D2-like receptors makes it a useful tool for dissecting the contributions of different dopamine receptor subtypes to behavior. However, the compound's effects can vary depending on the dose, route of administration, and experimental paradigm.

In vitro receptor binding assays for (-)-quinpirole hydrochloride measure its affinity for dopamine receptor subtypes. Radioligand binding studies are performed using membrane preparations from cells or tissues expressing dopamine receptors and radiolabeled selective ligands. For D2-like receptors, [³H]-raclopride or [³H]-spiperone are commonly used as tracers. Competition binding experiments with varying concentrations of (-)-quinpirole hydrochloride determine its binding affinity (Ki) for each receptor subtype. For D1 receptors, [³H]-SCH23390 is used as a tracer. These assays are essential for characterizing the compound's selectivity and potency at different dopamine receptor subtypes.

In vitro cell-based functional assays for (-)-quinpirole hydrochloride evaluate its agonist activity at dopamine receptors. Cells expressing recombinant dopamine receptors (D1, D2, D3, D4) are treated with varying concentrations of the compound. For D2-like receptors (D2, D3, D4), which are coupled to Gi/o proteins, agonist activity is assessed by measuring inhibition of forskolin-stimulated cAMP accumulation using ELISA or FRET-based assays. For D1 receptors, which are coupled to Gs proteins, agonist activity is assessed by measuring cAMP accumulation. Alternatively, GTPγS binding assays can be used to measure receptor activation. These assays confirm the compound's agonist activity and provide data on its potency and efficacy at each receptor subtype.

Rat: After giving injections of either saline or Quinpirole (Hydrochloride) (0.5 mg/kg, s.c., n = 18/condition) to 36 male Long-Evans rats every day for 12 days, the rats are promptly placed in Omnitech activity monitors (60×60×40 cm) for a 90-minute period. n=9/group) of rats in each chronic condition were given saline and half quinpirole on the last test day. Thus, the four groups stood for sensitized Quinpirole (drug) (QQ), acute Quinpirole (SQ), sensitized Quinpirole (no drug) (QS), and saline controls (SS). Thirty minutes following the last injection, every rat is taken out of the activity monitors and brought to a nearby room where it is promptly beheaded. Since acute quinpirole inhibits activity at this time, and chronic quinpirole is linked to marked hyperlocomotion at 30 minutes, this time point is selected to disentangle the behavioral effects of quinpirole between groups[1].

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In vivo animal studies for (-)-quinpirole hydrochloride are conducted to evaluate its behavioral and physiological effects. In typical studies, rodents are administered the compound via intraperitoneal or subcutaneous injection, and locomotor activity is measured using open field or activity chamber tests. The compound's effects on other behaviors, such as stereotypic behavior, grooming, and cognitive performance, can also be assessed. The compound's effects on neurochemical parameters, such as dopamine turnover and release, can be measured using microdialysis or tissue analysis. These studies are essential for understanding the functional consequences of D2-like receptor activation and for validating the compound's utility as a pharmacological tool.

(-)-Quinpirole hydrochloride has a molecular weight of 255.79 and a chemical formula of C₁₃H₂₁N₃·HCl. As a small molecule with a hydrochloride salt form, it is water-soluble and suitable for parenteral administration in animal studies. The compound is typically administered via intraperitoneal or subcutaneous injection. Detailed pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion are established in the pharmacological literature. The compound is metabolized in the liver and excreted renally. Its ability to cross the blood-brain barrier allows it to reach its central nervous system targets. Storage conditions are typically -20°C, protected from light.

Intraperitoneal injection of LDLo 800 mg/kg in mice, Journal of Medicinal Chemistry, 26(1112), 1983.

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Specific toxicity data for (-)-quinpirole hydrochloride is not extensively reported in the publicly available literature. As a selective dopamine D2 receptor agonist, the compound's safety profile would depend on the role of D2 receptors in various physiological functions. Potential side effects may include those associated with dopaminergic stimulation, such as nausea, vomiting, hypotension, and behavioral changes. At high doses, the compound may cause motor effects such as stereotypy or dyskinesia. The compound is classified as a research-grade chemical and is not intended for human use. Standard laboratory safety precautions should be followed when handling (-)-quinpirole hydrochloride.

[1]. Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats. Neuroscience. 1998 Apr;83(3):781-9.

[2]. Decrease in hypothalamic epinephrine concentration and other neurochemical changes produced by quinpirole, a dopamine agonist, in rats. J Neural Transm . 1985;61(3-4):161-73.

Dopamine D2/D3 receptor agonists. This study investigated post-mortem changes in central dopaminergic nerve endings following acute or chronic treatment with the dopamine D2/D3 receptor agonist quinpyrrole (a psychomotor stimulant that can significantly induce behavioral sensitization with long-term use). Drug-induced changes in the nucleus accumbens, striatum, and amygdala were bilateral, while the left and right hemispheres of the prefrontal cortex (medial prefrontal cortex and anterior cingulate cortex) responded differently to quinpyrrole. Acute drug treatment increased tissue levels of dopamine in the nucleus accumbens and right prefrontal cortex, while decreasing the dopamine metabolite 3,4-dihydroxyphenylacetic acid (3,4-DPA) in the amygdala. Conversely, quinpyrrole sensitization was associated with decreased dopamine levels in the left prefrontal cortex and increased levels of 3,4-DPA in subcortical structures, particularly the striatum and amygdala. Furthermore, the increase in 3,4-DPA in the striatum of chronically quinpyrrole-treated animals was independent of the last drug injection. In summary, quetiapine can induce multiple concurrent regional changes in dopaminergic function, with sensitization primarily associated with the upregulation of subcortical dopamine activity. Although the nucleus accumbens and striatum play well-known roles in motor activation and sensitized behavior, the study concluded that the amygdala and prefrontal cortex have significant regulatory roles in these processes, and that the role of the prefrontal cortex is inherently asymmetrical. Given the correlation between behavioral sensitization and human psychopathological states, the current data have been compared with clinical findings, particularly with obsessive-compulsive disorder. [1]

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(-)-Quinpirole hydrochloride (CAS# 85798-08-9) is a selective dopamine D2 receptor agonist with high affinity for D2 (Ki = 4.8 nM) and D3 (approximately 24 nM) receptors. It has moderate affinity for D4 (approximately 30 nM) and low affinity for D1 (1900 nM) receptors. The compound inhibits locomotor activity and serves as an important tool for studying dopamine-related processes and neurological disorders. It has a molecular weight of 255.79. (-)-Quinpirole hydrochloride is a research-grade compound and has not received FDA approval for any indication.

C13H22CLN3

255.78688

255.15

C, 61.04; H, 8.67; Cl, 13.86; N, 16.43

85798-08-9

80373-22-4; 85798-08-9 (HCl); 73625-62-4 (2HCl)

55397

White to off-white solid powder

1.07g/cm3

383.9ºC at 760 mmHg

186ºC

1.546

2.738

2

2

2

17

243

2

C(N1CCC[C@@H]2CC3NN=CC=3C[C@@H]12)CC.Cl

HJHVRVJTYPKTHX-HTMVYDOJSA-N

InChI=1S/C13H21N3.ClH/c1-2-5-16-6-3-4-10-7-12-11(8-13(10)16)9-14-15-12;/h9-10,13H,2-8H2,1H3,(H,14,15);1H/t10-,13-;/m1./s1

(4aR,8aR)-5-propyl-1,4,4a,6,7,8,8a,9-octahydropyrazolo[3,4-g]quinoline;hydrochloride

LY-171555; LY 171555; LY171555; (-)Quinpirole hydrochloride; (-)-Quinpirole HCl; (-)Quinpirole HCl; (-)-Quinpirole hydrochloride; 85798-08-9; QUINPIROLE HYDROCHLORIDE; Quinpirole HCl; Quinpirole hydrochloride [USAN]; T6I2W5V2K1; (-) Quinpirole HCl

2934.99.03.00

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)

H2O: ~50 mg/mL (~195.5 mM)
DMSO: ~27.8 mg/mL (~108.6 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (8.13 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 20.8 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: ≥ 2.08 mg/mL (8.13 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 20.8 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: ≥ 2.08 mg/mL (8.13 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (390.95 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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