Quipazine dimaleate is a 5-HT agonist, displacing 5-HT3R in rat endothelium [3H]GR65630 with a Ki of 1.4 nM. Quipazine dimaleate has antiviral effect against SARS-CoV-2 with EC50 of 31.64 μM. Quipazine dimaleate works as a 5-HT3R antagonist in peripheral models and may be utilized to study neurological diseases.

Physicochemical Properties

Molecular Formula	C21H23N3O8
Molecular Weight	445.42
Exact Mass	445.149
Elemental Analysis	C, 56.63; H, 5.20; N, 9.43; O, 28.73
CAS #	150323-78-7
Related CAS #	Quipazine;4774-24-7; 150323-78-7 (dimaleate); 5786-68-5
PubChem CID	6420043
Appearance	White to off-white solid powder
LogP	1.461
Hydrogen Bond Donor Count	5
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	5
Heavy Atom Count	32
Complexity	344
Defined Atom Stereocenter Count	0
SMILES	C(O)(=O)/C=C/C(O)=O.N1(C2C=CC3C(=CC=CC=3)N=2)CCNCC1.C(O)(=O)/C=C/C(O)=O
InChi Key	VAOSOCRJSSWBEQ-SPIKMXEPSA-N
InChi Code	InChI=1S/C13H15N3.2C4H4O4/c1-2-4-12-11(3-1)5-6-13(15-12)16-9-7-14-8-10-16;2*5-3(6)1-2-4(7)8/h1-6,14H,7-10H2;2*1-2H,(H,5,6)(H,7,8)/b;2*2-1-
Chemical Name	2-(1-Piperazinyl)quinoline dimaleate
Synonyms	Quipazine dimaleate; 150323-78-7; 2-(1-Piperazinyl)quinoline dimaleate; Quipazine (dimaleate); Quipazine dimaleate salt; 2-(piperazin-1-yl)quinoline dimaleate; (Z)-but-2-enedioic acid;2-piperazin-1-ylquinoline; Prestwick_905
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	5-HT receptors
ln Vitro	Quipazine dimaleate exhibits 230 nM Ki values and binding potency for both 5-HT1 and 5-HT2 [3]. With a Ki value of 1.4 nM, quipazine dimaleate replaces [3H]GR65630 at 5-HT3R in rat endothelium [3]. The rat vagus nerve is antagonistically affected by quipazine dimaleate; its pIC50 values for 5-HT2, 5-HT1, and inhibition of 5-HT release are, respectively, 6.1, 6.49, and 6.17 [4].
ln Vivo	In male and female rats, quipazine dimaleate (2.5, 5, and 7.5 mg/kg, once each; i.p.) influences the nutritional self-selection of various macronutrient diets [1]. Macronutrient intakes, 2h and 12h, following administration of a selective 5-HT3 agonist, quipazine, N methyl, dimaleate (QUIPAZINE; 2.5, 5.0 and 7.5 mg/kg, i.p.) at dark onset were examined in three groups of adult male and female Wistar rats fed different sources of the three macronutrients: Group 1 (casein, corn starch, safflower oil), Group 2 (egg protein, corn starch/sucrose, lard) and Group S (casein hydrolysate, maltose dextrin, butter). QUIPAZINE decreased total food intake only in female rats from Group 1 (2 h) at a dose of 7.5 mg/kg and Group 2 (2h and 12h) with doses of 2.5 and 7.5 mg/kg. Intakes from corn starch and corn starch/sucrose diet (12h) were reduced in male and female rats, respectively, with doses of 2.5 and 7.5 mg/kg of QUIPAZINE. In conclusion, when provided with different sources of the three macronutrients, quipazine injection reduces specifically carbohydrate ingestion from corn starch-containing diets in male and female rats. Thus, the nature of the macronutrient source is of major importance to assess the effect of a drug on nutrient-specific selection. [1]
Enzyme Assay	Arylpiperazines, such as 1-(3-trifluoromethylphenyl)piperazine (TFMPP) and its chloro analogue mCPP, are 5-HT1 agonists, whereas quipazine, i.e., 2-(1-piperazino)quinoline, appears to be a 5-HT2 agonist. Radioligand binding studies using rat cortical membrane homogenates and drug discrimination studies using rats trained to discriminate a 5-HT1 agonist (i.e., TFMPP) or a 5-HT2 agonist (i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM)) from saline reveal that quipazine and its 1-deaza analogue 2-naphthylpiperazine (2-NP) bind at 5-HT1 and 5-HT2 sites but produce stimulus effects similar to those of DOM. A structurally related compound, 1-naphthylpiperazine (1-NP), possesses a high affinity for 5-HT1 (Ki = 5 nM) and 5-HT2 (Ki = 18 nM) sites. 1-NP produces stimulus effects similar to those of TFMPP and is able to antagonize the stimulus effects produced by DOM. The present results suggest that the unsubstituted benzene ring of quipazine, and of its 1-deaza analogue 2-naphthylpiperazine, makes a significant contribution to the binding of these agents to 5-HT2 sites and, more importantly, may account for their 5-HT2 agonist properties. [3]
Animal Protocol	Animal/Disease Models: Male and female Wistar rats feed with different sources of the three macronutrients (Group 1: casein, corn starch, safflower oil. Group 2: egg protein , corn starch/sucrose, lard. Group S: casein hydrolysate, maltose dextrin, butter.)[1] Doses: 2.5, 5 and 7.5 mg/kg Route of Administration: intraperitoneal (ip)injection; 2.5, 5 and 7.5 mg/kg, one dose for once Experimental Results: Increased water intake and food intake of male rats from Group S, and diminished food intake of female rats from Group 1 and Group 2s at 2h post-injection. diminished food intake in female rats from Group 2, diminished protein intake in female rats from Group 1. Rats were given 10 days to adapt to the diets and the environment. For the initial 3 days of adaptation rats were allowed ad libitum access to the diets. In order to habituate rats to a similar 4-h food deprivation as during the injection days, rats were subsequently adapted to a daily 4-h food deprivation period between 1600h and 2000h during the remaining seven days of adaptation. Body weights, water and macronutrient intakes during the 12-h dark phase were measured daily during the 10 days of adaptation. On injection days, following a 4-h food deprivation, rats from the three dietary groups received i.p. injections at dark onset (2000h) of either physiological saline (0 9% NaCl) or Quipazine, N-methyl, dimaleate (QUIPAZINE, RBI) dissolved in physiological saline. Macronutrient and water intakes were measured at 2 h and 12 h following injections. Drug doses were given in the following order: saline, 2 5 mg/kg, 5 0 mg/kg and 7 5 mg/kg Quipazine. In order to avoid possible down regulation of 5-HT receptors following higher doses of Quipazine, the drug dosage was administered in ascending order rather than counterbalanced. Drug injection days were separated by 48 h. Basal self-selection profiles for each of the three dietary groups were resumed before subsequent injections. Contrast comparisons revealed no difference between 12 h basal macronutrient intakes for each of the three dietary groups and 12 h macronutrient intakes on washout days. [1]
Toxicity/Toxicokinetics	mouse LD50 oral 296 mg/kg Drug Development Research., 3(357), 1983 mouse LD50 intraperitoneal 135 mg/kg Journal of Medicinal Chemistry., 28(1394), 1985
References	[1]. Effect of quipazine, a selective 5-HT3 agonist, on dietary self-selection of different macronutrient diets in male and female rats. Appetite. 2000 Jun;34(3):313-25. [2]. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science. 2021 May 7;372(6542):642-646. [3]. 5-HT1 and 5-HT2 binding characteristics of some quipazine analogues. J Med Chem. 1986 Nov;29(11):2375-80. [4]. Ireland SJ, Tyers MB. Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve. Br J Pharmacol. 1987 Jan;90(1):229-38.
Additional Infomation	2-(1-piperazinyl)quinoline is a member of pyridines and a member of piperazines. Quipazine is a piperazine-based nonselective serotonin (5-HT) receptor agonist with antidepressant and oxytocic activities. Quipazine targets and binds to serotonin receptors, particularly to the 5HT2A and 5HT3 receptors. Serotonin receptor activation by quipazine may lead to smooth muscle contraction and antidepressant effects. A pharmacologic congener of serotonin that contracts smooth muscle and has actions similar to those of tricyclic antidepressants. It has been proposed as an oxytocic. The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2. [2] A study has been made of the pharmacology of the 5-hydroxytryptamine (5-HT)-induced depolarization responses that can be recorded extracellularly from the rat isolated cervical vagus nerve. Phenylbiguanide (PBG) and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) were found to mimic the effects of 5-HT on the vagus nerve. Their EC50 values were respectively 2.0 fold and 3.9 fold greater than that of 5-HT. Metoclopramide behaved as a reversible competitive antagonist of depolarization induced by PBG and 2-methyl-5-HT, with pKB values of 6.48 +/- 0.04, respectively. These agreed well with the pKB value of 6.60 +/- 0.04 obtained previously for metoclopramide against 5-HT on the rat vagus nerve. 5-HT, PBG and 2-methyl-5-HT had no demonstrable agonist effects at non-5-HT receptors on the rat vagus nerve. Tropacaine and m-chlorophenylpiperazine were found to behave as reversible competitive antagonists of 5-HT-induced depolarization of the vagus nerve. The pKB values were 6.29 +/- 0.03 and 6.90 +/- 0.03, respectively. Quipazine, MDL 72222 and ICS 205-930 were also shown to be effective antagonists of 5-HT on the vagus nerve. However, although these compounds were highly potent, they all caused a marked concentration-dependent reduction in the amplitude of the maximum response to 5-HT. This behaviour was not consistent with a simple reversible competitive mechanism. The results are discussed with reference to the current classification of mammalian peripheral neuronal 5-HT receptors. [4]

Solubility Data

Solubility (In Vitro)

DMSO : 250 mg/mL (561.27 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.67 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2451 mL	11.2254 mL	22.4507 mL
	5 mM	0.4490 mL	2.2451 mL	4.4901 mL
	10 mM	0.2245 mL	1.1225 mL	2.2451 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.