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MedKoo Cat#: 326801 | Name: Stepholidine
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Description:

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

Stepholidine is a naturally occurring chemical compound found in the herb Stephania intermedia. Stepholidine is a dual D2 receptor antagonist and D1 receptor agonist, and has shown antipsychotic activity in animal studies.

Chemical Structure

Stepholidine
Stepholidine
CAS#16562-13-3

Theoretical Analysis

MedKoo Cat#: 326801

Name: Stepholidine

CAS#: 16562-13-3

Chemical Formula: C19H21NO4

Exact Mass: 327.1471

Molecular Weight: 327.38

Elemental Analysis: C, 69.71; H, 6.47; N, 4.28; O, 19.55

Price and Availability

Size Price Availability Quantity
1mg USD 730.00 2 weeks
5mg USD 2,350.00 2 weeks
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Synonym
Stepholidine; L-Stepholidine; (-)-Stepholidine; S-Stepholidine.
IUPAC/Chemical Name
(S)-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-2,10-diol
InChi Key
JKPISQIIWUONPB-HNNXBMFYSA-N
InChi Code
InChI=1S/C19H21NO4/c1-23-18-8-12-5-6-20-10-14-11(3-4-16(21)19(14)24-2)7-15(20)13(12)9-17(18)22/h3-4,8-9,15,21-22H,5-7,10H2,1-2H3/t15-/m0/s1
SMILES Code
OC1=C(OC)C=C(CCN2CC3=C(OC)C(O)=CC=C3C[C@]24[H])C4=C1
Appearance
Solid powder
Purity
>95% (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
>2 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
2934.99.9001
More Info
Product Data
Product Data
Instruction
View handling instruction
Biological target:
Stepholidine binds to dopamine D1, D2, D3, D4, and D5 receptors (Kis = 5.1, 11.6, 24, 1,450, and 5.8 nM, respectively) as well as 5-HT1A, 5-HT2B, α2C-adrenergic receptors (α2C-ARs), and sigma-2 (σ2) receptors in a radioligand binding assay (Kis = 143, 226, 215, and 53 nM, respectively). It inhibits dopamine-induced cAMP accumulation in HEK293 cells expressing dopamine D1, D2, and D5 receptors with IC50 values of 20.5, 128, and 27 nM, respectively. Stepholidine inhibits forskolin-induced cAMP production in CHO cells expressing rat 5-HT1A receptors (EC50 = 1.2 μM).
In vitro activity:
Stepholidine acts as a pan-dopamine receptor antagonist, showing high affinity for D1 and D5 receptors, lower affinity for D2 and D3 receptors, and low micromolar affinity for D4 receptors. Stepholidine did not activate G protein-mediated signaling or stimulate β-arrestin recruitment to any dopamine receptor subtype but did antagonize these responses. It also antagonized D1-D2 heteromer-mediated Ca(2+) mobilization and binded to D1 receptors with antagonist-like properties. Reference: Psychopharmacology (Berl). 2015 Mar;232(5):917-30. https://pubmed.ncbi.nlm.nih.gov/25231919/
In vivo activity:
Stepholidine may be a potential treatment for cue-driven aspects of cocaine use disorder. In a murine model of cocaine addiction, a preference test showed that each stepholidine group maintained a conditioned place preference (CPP) similar to the vehicle group. These data indicate that stepholidine can block the expression of a cocaine CPP but has no effect on its development, suggesting that it inhibits the effects of cocaine cues on cocaine incentive motivated behavior. Reference: Neurosci Lett. 2020 Aug 24;734:135151. https://pubmed.ncbi.nlm.nih.gov/32531529/
Solvent mg/mL mM
Solubility
DMF 5.0 15.27
DMSO 5.0 15.27
Ethanol 1.1 3.36
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 327.38 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.

Recalculate based on batch purity %
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:
1. Meade JA, Free RB, Miller NR, Chun LS, Doyle TB, Moritz AE, Conroy JL, Watts VJ, Sibley DR. (-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and β-arrestin-mediated signaling. Psychopharmacology (Berl). 2015 Mar;232(5):917-30. doi: 10.1007/s00213-014-3726-8. Epub 2014 Sep 18. PMID: 25231919; PMCID: PMC5234683. 2. Guo H, Yu Y, Xing L, Jin GZ, Zhou J. (-)-Stepholidine promotes proliferation and neuronal differentiation of rat embryonic striatal precursor cells in vitro. Neuroreport. 2002 Nov 15;13(16):2085-9. doi: 10.1097/00001756-200211150-00019. PMID: 12438931. 3. Bennett A, Barrera E, Namballa H, Harding W, Ranaldi R. (-)-Stepholidine blocks expression, but not development, of cocaine conditioned place preference in rats. Neurosci Lett. 2020 Aug 24;734:135151. doi: 10.1016/j.neulet.2020.135151. Epub 2020 Jun 9. PMID: 32531529; PMCID: PMC7368993. 4. Manuszak M, Harding W, Gadhiya S, Ranaldi R. (-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine self-administration in rats. Drug Alcohol Depend. 2018 Aug 1;189:49-54. doi: 10.1016/j.drugalcdep.2018.04.030. Epub 2018 May 31. PMID: 29879681; PMCID: PMC6062455.
In vitro protocol:
1. Meade JA, Free RB, Miller NR, Chun LS, Doyle TB, Moritz AE, Conroy JL, Watts VJ, Sibley DR. (-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and β-arrestin-mediated signaling. Psychopharmacology (Berl). 2015 Mar;232(5):917-30. doi: 10.1007/s00213-014-3726-8. Epub 2014 Sep 18. PMID: 25231919; PMCID: PMC5234683. 2. Guo H, Yu Y, Xing L, Jin GZ, Zhou J. (-)-Stepholidine promotes proliferation and neuronal differentiation of rat embryonic striatal precursor cells in vitro. Neuroreport. 2002 Nov 15;13(16):2085-9. doi: 10.1097/00001756-200211150-00019. PMID: 12438931.c
In vivo protocol:
1. Bennett A, Barrera E, Namballa H, Harding W, Ranaldi R. (-)-Stepholidine blocks expression, but not development, of cocaine conditioned place preference in rats. Neurosci Lett. 2020 Aug 24;734:135151. doi: 10.1016/j.neulet.2020.135151. Epub 2020 Jun 9. PMID: 32531529; PMCID: PMC7368993. 2. Manuszak M, Harding W, Gadhiya S, Ranaldi R. (-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine self-administration in rats. Drug Alcohol Depend. 2018 Aug 1;189:49-54. doi: 10.1016/j.drugalcdep.2018.04.030. Epub 2018 May 31. PMID: 29879681; PMCID: PMC6062455.
1: Li W, Zhang L, Xu L, Yuan C, Du P, Chen J, Zhen X, Fu W. Functional reversal of (-)-Stepholidine analogues by replacement of benzazepine substructure using the ring-expansion strategy. Chem Biol Drug Des. 2016 May 27. doi: 10.1111/cbdd.12796. [Epub ahead of print] PubMed PMID: 27232055. 2: Gadhiya SV, Hu C, Harding WW. An alternative synthesis and x-ray crystallographic confirmation of (-)-stepholidine. Tetrahedron Lett. 2016 May 11;57(19):2090-2092. PubMed PMID: 27152055; PubMed Central PMCID: PMC4852479. 3: Hao JR, Sun N, Lei L, Li XY, Yao B, Sun K, Hu R, Zhang X, Shi XD, Gao C. L-Stepholidine rescues memory deficit and synaptic plasticity in models of Alzheimer's disease via activating dopamine D1 receptor/PKA signaling pathway. Cell Death Dis. 2015 Nov 5;6:e1965. doi: 10.1038/cddis.2015.315. PubMed PMID: 26539912; PubMed Central PMCID: PMC4670924. 4: Meade JA, Free RB, Miller NR, Chun LS, Doyle TB, Moritz AE, Conroy JL, Watts VJ, Sibley DR. (-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and β-arrestin-mediated signaling. Psychopharmacology (Berl). 2015 Mar;232(5):917-30. doi: 10.1007/s00213-014-3726-8. Epub 2014 Sep 18. PubMed PMID: 25231919. 5: Ma B, Yue K, Chen L, Tian X, Ru Q, Gan Y, Wang D, Jin G, Li C. L-stepholidine, a natural dopamine receptor D1 agonist and D2 antagonist, inhibits heroin-induced reinstatement. Neurosci Lett. 2014 Jan 24;559:67-71. doi: 10.1016/j.neulet.2013.10.066. Epub 2013 Nov 20. PubMed PMID: 24269875. 6: Yue K, Ma B, Chen L, Tian X, Ru Q, Gan Y, Wang D, Jin G, Li C. L-Stepholidine, a naturally occurring dopamine D1 receptor agonist and D2 receptor antagonist, attenuates heroin self-administration and cue-induced reinstatement in rats. Neuroreport. 2014 Jan 8;25(1):7-11. doi: 10.1097/WNR.0000000000000012. PubMed PMID: 24145772. 7: Li B, Li W, Du P, Yu KQ, Fu W. Molecular insights into the D1R agonist and D2R/D3R antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations. J Phys Chem B. 2012 Jul 19;116(28):8121-30. doi: 10.1021/jp3049235. Epub 2012 Jul 3. PubMed PMID: 22702398. 8: Gao M, Chu HY, Jin GZ, Zhang ZJ, Wu J, Zhen XC. l-Stepholidine-induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5-HT(1A) receptor partial agonistic activity. Synapse. 2011 May;65(5):379-87. doi: 10.1002/syn.20855. Epub 2010 Sep 24. PubMed PMID: 20803620. 9: Cheng JJ, Yang YS. Enantioselective total synthesis of (-)-(S)-stepholidine. J Org Chem. 2009 Dec 4;74(23):9225-8. doi: 10.1021/jo9020826. PubMed PMID: 19950885. 10: Sun Y, Dai J, Hu Z, Du F, Niu W, Wang F, Liu F, Jin G, Li C. Oral bioavailability and brain penetration of (-)-stepholidine, a tetrahydroprotoberberine agonist at dopamine D(1) and antagonist at D(2) receptors, in rats. Br J Pharmacol. 2009 Nov;158(5):1302-12. doi: 10.1111/j.1476-5381.2009.00393.x. Epub 2009 Sep 25. PubMed PMID: 19788498; PubMed Central PMCID: PMC2782339. 11: Guo Y, Zhang H, Chen X, Cai W, Cheng J, Yang Y, Jin G, Zhen X. Evaluation of the antipsychotic effect of bi-acetylated l-stepholidine (l-SPD-A), a novel dopamine and serotonin receptor dual ligand. Schizophr Res. 2009 Nov;115(1):41-9. doi: 10.1016/j.schres.2009.08.002. Epub 2009 Sep 9. PubMed PMID: 19744833. 12: Qiu MH, Qu WM, Xu XH, Yan MM, Urade Y, Huang ZL. D(1)/D(2) receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice. Pharmacol Biochem Behav. 2009 Nov;94(1):16-23. doi: 10.1016/j.pbb.2009.06.018. Epub 2009 Jul 12. PubMed PMID: 19604496. 13: Mo J, Zhang H, Yu LP, Sun PH, Jin GZ, Zhen X. L-stepholidine reduced L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease. Neurobiol Aging. 2010 Jun;31(6):926-36. doi: 10.1016/j.neurobiolaging.2008.06.017. Epub 2008 Aug 15. PubMed PMID: 18707801. 14: Natesan S, Reckless GE, Barlow KB, Odontiadis J, Nobrega JN, Baker GB, George SR, Mamo D, Kapur S. The antipsychotic potential of l-stepholidine--a naturally occurring dopamine receptor D1 agonist and D2 antagonist. Psychopharmacology (Berl). 2008 Aug;199(2):275-89. doi: 10.1007/s00213-008-1172-1. Epub 2008 Jun 3. PubMed PMID: 18521575. 15: Mo J, Guo Y, Yang YS, Shen JS, Jin GZ, Zhen X. Recent developments in studies of l-stepholidine and its analogs: chemistry, pharmacology and clinical implications. Curr Med Chem. 2007;14(28):2996-3002. Review. PubMed PMID: 18220736. 16: Yang K, Jin G, Wu J. The neuropharmacology of (-)-stepholidine and its potential applications. Curr Neuropharmacol. 2007 Dec;5(4):289-94. doi: 10.2174/157015907782793649. PubMed PMID: 19305745; PubMed Central PMCID: PMC2644490. 17: Gu WH, Yang S, Shi WX, Zhen XC, Jin GZ. Effects of (-)-stepholidine on NMDA receptors: comparison with haloperidol and clozapine. Acta Pharmacol Sin. 2007 Jul;28(7):953-8. PubMed PMID: 17588330. 18: Fu W, Shen J, Luo X, Zhu W, Cheng J, Yu K, Briggs JM, Jin G, Chen K, Jiang H. Dopamine D1 receptor agonist and D2 receptor antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations. Biophys J. 2007 Sep 1;93(5):1431-41. Epub 2007 Apr 27. PubMed PMID: 17468175; PubMed Central PMCID: PMC1948031. 19: Gao M, Liu CL, Yang S, Zhen XC, Jin GZ. l-Stepholidine increases the frequency of sEPSC via the activation of D1 dopamine signaling pathway in rat prelimbic cortical neurons. Acta Pharmacol Sin. 2007 May;28(5):627-33. PubMed PMID: 17439718. 20: Odontiadis J, MacKenzie EM, Natesan S, Mamo D, Kapur S, Baker GB. Quantification of l-stepholidine in rat brain and plasma by high performance liquid chromatography combined with fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 1;850(1-2):544-7. Epub 2006 Dec 11. PubMed PMID: 17161981.