Metoprine | 7761-45-7 | folate antagonist

MedKoo Cat#: 581348 | Name: Metoprine

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Metoprine is a diaminopyrimidine folate antagonist with potential antineoplastic activity. Metoprine inhibits dihydrofolate reductase, resulting in decreased cellular folate metabolism and cell growth; it also inhibits histamine-N-methyltransferase, resulting in decreased histamine catabolism. Lipid-soluble metoprine is capable of crossing the blood-brain barrier.

Chemical Structure

Metoprine

CAS#7761-45-7

Theoretical Analysis

MedKoo Cat#: 581348

Name: Metoprine

CAS#: 7761-45-7

Chemical Formula: C11H10Cl2N4

Exact Mass: 268.0283

Molecular Weight: 269.13

Elemental Analysis: C, 49.09; H, 3.75; Cl, 26.34; N, 20.82

Price and Availability

Size	Price	Availability
10mg	USD 110.00	Ready to ship
25mg	USD 220.00	Ready to ship
50mg	USD 400.00	Ready to ship
100mg	USD 700.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 3,650.00	Ready to ship
2g	USD 5,950.00	Ready to ship

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Synonym

Metoprine; DDMP; Methodichlorophen; Metoprine; BW 197U; BW-197U; BW197U;

IUPAC/Chemical Name

2,4-Diamino-5-(3',4'-dichlorophenyl)-6-methyl pyrimidine

InChi Key

VQJHOPSWBGJHQS-UHFFFAOYSA-N

InChi Code

InChI=1S/C11H10Cl2N4/c1-5-9(10(14)17-11(15)16-5)6-2-3-7(12)8(13)4-6/h2-4H,1H3,(H4,14,15,16,17)

SMILES Code

CC1=C(C2=CC=C(Cl)C(Cl)=C2)C(N)=NC(N)=N1

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>3 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.03.00

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A20T08K28

QC Data

View QC data: current batch, Lot#A20T08K28

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

In vitro activity:

Metoprine was capable of replacing trimetrexate and exhibits slightly greater inhibitory activity in combination than trimetrexate. Both metoprine and trimetrexate in combination with PDDF caused synergistic inhibition of the de novo synthesis of thymidylate in intact cells as measured by tritium release from [5-3H]deoxyuridine. Clonal assays were used to demonstrate synergy between trimetrexate or metoprine and PDDF, attesting to the cytotoxic properties of this combination. Thymidine alone can protect against both the synergistic combination of trimetrexate or metoprine and PDDF and PDDF alone, but has only a weak protective effect on toxic concentrations of trimetrexate and metoprine. Reference: Cancer Res. 1987 Oct 15;47(20):5256-60. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=2958130

In vivo activity:

The effects of metoprine, an inhibitor of histamine N-methyltransferase, on open field activity and brain regional histamine (HA) content were examined in rats with mixed, absence and audiogenic, epilepsy (WAG/Rij-AGS), rats with audiogenic epilepsy (Wistar-AGS) and in non-epileptic control rats (Wistar-nAGS). HA content was increased by metoprine (20mg/kg, i.p.) in the cortex, striatum, thalamus, hypothalamus and hippocampus of the rats from all three tested groups. However, WAG/Rij rats showed a lower rate of metoprine-induced HA accumulation in the striatum and thalamus than Wistar rats. For the open field test, the main effect of metoprine (20mg/kg, i.p.) was a general increase of locomotor activity although distinctive features, such as hyperlocomotion and exaggerated sniffing, were characteristic for the epileptic rats (WAG/Rij-AGS and Wistar-AGS, respectively). Individual rats from all the groups showed stereotyped behavior of shuttle type and head bobbing. Electroencephalographic data obtained in WAG/Rij-AGS rats confirmed that metoprine-induced behavioral activation was accompanied by suppression of spike-wave discharges, the main hallmark of absence seizures. Reference: Epilepsy Res. 2012 Aug;101(1-2):148-56. https://linkinghub.elsevier.com/retrieve/pii/S0920-1211(12)00091-5

	Solvent	mg/mL	mM
Solubility
	DMSO	20.8	77.40

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 269.13 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

1. Galivan J, Nimec Z, Rhee M. Synergistic growth inhibition of rat hepatoma cells exposed in vitro to N10-propargyl-5,8-dideazafolate with methotrexate or the lipophilic antifolates trimetrexate or metoprine. Cancer Res. 1987 Oct 15;47(20):5256-60. PMID: 2958130.

In vivo protocol:

1. Samotaeva IS, Birioukova LM, Midzyanovskaya IS, Kuznetsova GD, Bazyan AS, Tuomisto L. Metoprine induced behavioral modifications and brain regional histamine increase in WAG/Rij and Wistar rats. Epilepsy Res. 2012 Aug;101(1-2):148-56. doi: 10.1016/j.eplepsyres.2012.03.016. Epub 2012 Apr 12. PMID: 22503455.

1: Samotaeva IS, Birioukova LM, Midzyanovskaya IS, Kuznetsova GD, Bazyan AS, Tuomisto L. Metoprine induced behavioral modifications and brain regional histamine increase in WAG/Rij and Wistar rats. Epilepsy Res. 2012 Aug;101(1-2):148-56. doi: 10.1016/j.eplepsyres.2012.03.016. Epub 2012 Apr 12. PMID: 22503455. 2: Lecklin A, Tuomisto L, MacDonald E. Metoprine, an inhibitor of histamine N-methyltransferase but not catechol-O-methyltransferase, suppresses feeding in sated and in food deprived rats. Methods Find Exp Clin Pharmacol. 1995 Jan- Feb;17(1):47-52. PMID: 7542717. 3: Sirotnak FM, Moccio DM, Goutas LJ, Kelleher LE, Montgomery JA. Biochemical correlates of responsiveness and collateral sensitivity of some methotrexate- resistant murine tumors to the lipophilic antifolate, metoprine. Cancer Res. 1982 Mar;42(3):924-8. PMID: 7059991. 4: Malmberg-Aiello P, Ipponi A, Bartolini A, Schunack W. Antiamnesic effect of metoprine and of selective histamine H(1) receptor agonists in a modified mouse passive avoidance test. Neurosci Lett. 2000 Jul 7;288(1):1-4. doi: 10.1016/s0304-3940(00)01176-9. PMID: 10869801. 5: Jochem J. Cardiac and regional haemodynamic effects of histamine N-methyltransferase inhibitor metoprine in haemorrhage-shocked rats. Inflamm Res. 2004 Jul;53(7):316-23. doi: 10.1007/s00011-004-1268-y. Epub 2004 Jun 25. PMID: 15241567. 6: Lecklin A, Eriksson L, Leppäluoto J, Tarhanen J, Tuomisto L. Metoprine- induced thirst and diuresis in Wistar rats. Acta Physiol Scand. 1999 Mar;165(3):325-33. doi: 10.1046/j.1365-201X.1999.00513.x. PMID: 10192183. 7: Galivan J, Nimec Z, Rhee M. Synergistic growth inhibition of rat hepatoma cells exposed in vitro to N10-propargyl-5,8-dideazafolate with methotrexate or the lipophilic antifolates trimetrexate or metoprine. Cancer Res. 1987 Oct 15;47(20):5256-60. PMID: 2958130. 8: Cavallito JC, Nichol CA, Brenckman WD Jr, Deangelis RL, Stickney DR, Simmons WS, Sigel CW. Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man. Drug Metab Dispos. 1978 May-Jun;6(3):329-37. PMID: 26555. 9: Lecklin A, Järvikylä M, Tuomisto L. The effect of metoprine on glucoprivic feeding induced by 2-deoxy-D-glucose. Pharmacol Biochem Behav. 1994 Dec;49(4):853-7. doi: 10.1016/0091-3057(94)90234-8. PMID: 7886098. 10: Sakai N, Onodera K, Maeyama K, Yanai K, Watanabe T. Effects of (S)-alpha -fluoromethylhistidine and metoprine on locomotor activity and brain histamine content in mice. Life Sci. 1992;51(6):397-405. doi: 10.1016/0024-3205(92)90406-f. PMID: 1635419. 11: Kitanaka J, Kitanaka N, Tatsuta T, Morita Y, Takemura M. Blockade of brain histamine metabolism alters methamphetamine-induced expression pattern of stereotypy in mice via histamine H1 receptors. Neuroscience. 2007 Jul 13;147(3):765-77. doi: 10.1016/j.neuroscience.2007.05.006. Epub 2007 Jun 14. PMID: 17570600. 12: Zawilska J, Nowak JZ. Changes in the rat brain histamine content following metoprine and other histamine-methyltransferase (HMT) inhibitors. Pol J Pharmacol Pharm. 1985 Nov-Dec;37(6):821-30. PMID: 3832018. 13: Galivan J, Nimec Z, Rhee M, Boschelli D, Oronsky AL, Kerwar SS. Antifolate drug interactions: enhancement of growth inhibition due to the antipurine 5,10-dideazatetrahydrofolic acid by the lipophilic dihydrofolate reductase inhibitors metoprine and trimetrexate. Cancer Res. 1988 May 1;48(9):2421-5. PMID: 2965613. 14: Serano RD, Sigel CW, Nichol CA, Bigner DD. Evaluation of the lipid-soluble diaminopyrimidines, metoprine and etoprine, in the avian sarcoma virus rat glioma model. Cancer Treat Rep. 1982 Jan;66(1):99-106. PMID: 6272992. 15: Hough LB, Khandelwal JK, Green JP. Inhibition of brain histamine metabolism by metoprine. Biochem Pharmacol. 1986 Jan 15;35(2):307-10. doi: 10.1016/0006-2952(86)90530-7. PMID: 3942601. 16: Jochem J, Irman-Florjanc T, Zwirska-Korczala K. The role of peripherally acting histamine in metoprine-induced reversal of haemorrhagic hypotension in rats--skeletal muscle microcirculatory studies. Inflamm Res. 2005 Apr;54 Suppl 1:S70-1. doi: 10.1007/s00011-004-0432-8. PMID: 15928841. 17: Jones BR, Gordon CS, Umans J, Reidenberg MM, Young CW. Kinetics of metoprine, a lipid-soluble antifolate. Br J Clin Pharmacol. 1981 Nov;12(5):675-80. doi: 10.1111/j.1365-2125.1981.tb01288.x. PMID: 7332733; PMCID: PMC1401947. 18: Levin EM, Meyer RB Jr, Levin VA. Quantitative high-pressure liquid chromatographic procedure for the determination of plasma and tissue levels of 2,4-diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine (metoprine) and its application to the measurement of brain capillary permeability coefficients. J Chromatogr. 1978 Aug 21;156(1):181-7. doi: 10.1016/s0021-9673(00)83138-6. PMID: 689956. 19: Lecklin A, Tuomisto L. The blockade of H1 receptors attenuates the suppression of feeding and diuresis induced by inhibition of histamine catabolism. Pharmacol Biochem Behav. 1998 Mar;59(3):753-8. doi: 10.1016/s0091-3057(97)00465-6. PMID: 9512082. 20: de Jager R, Dupont D, Rodzynek JJ, Dorlet C, Lagrange G. Phase I clinical trial and pharmacology of 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (metoprine) (DDMP) and folinic acid (CF). Cancer Chemother Pharmacol. 1981;6(1):75-80. doi: 10.1007/BF00253013. PMID: 6974058.