5β-Dihydroprogesterone

5β-Dihydroprogesterone

5β-Dihydroprogesterone
Names
IUPAC name
5β-Pregnan-3,20-dione
Identifiers
ChemSpider
Jmol-3D images Image
PubChem
Properties
C21H32O2
Molar mass 316.47758 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

5β-Dihydroprogesterone (5β-DHP), also known as 5β-pregnan-3,20-dione, is an endogenous neurosteroid and an intermediate in the biosynthesis of pregnanolone and epipregnanolone from progesterone.[1][2][3] It is synthesized from progesterone by the enzyme 5β-reductase.[1][4] 5β-DHP has been found to act as a positive allosteric modulator of the GABAA receptor (albeit with an affinity for this receptor regarded as relatively low (in comparison to 3α-hydroxylated progesterone metabolites such as pregnanolone and allopregnanolone))[5] and also as a negative allosteric modulator of the GABAA-rho receptor.[6] In accordance with the former action, it is reported to possess anesthetic, anxiolytic, and antinociceptive effects.[5][7][8] 5β-DHP has been found to act as an agonist of the pregnane X receptor (PXR) as well (albeit weakly (EC50 >10,000 µM)),[9] and has been found to regulate uterine contractility through activation of this receptor.[10][11] Unlike 5α-dihydroprogesterone, 5β-DHP does not possess affinity for the progesterone receptor, and hence, is not a progestogen.[12]

A study found that 5β-DHP, but not progesterone, directly bound to and antagonized the oxytocin receptor at nanomolar concentrations, and it was suggested that this may be one of the mechanisms by which progesterone maintains pregnancy.[13][14][15] However, a subsequent study was unable to replicate this finding, and there has been no further investigation since.[14] In any case, 5β-DHP has nonetheless been shown to possess tocolytic effects in animals, and this may alternatively be mediated by activation of the PXR.[11]

See also

References

  1. ^ a b Neurosteroids and Brain Function. Academic Press. 12 December 2001. pp. 464–.  
  2. ^ Neurosteroids. Frontiers E-books. pp. 8–.  
  3. ^ Gilbert Evans, Susan E.; Ross, Lori E.; Sellers, Edward M.; Purdy, Robert H.; Romach, Myroslava K. (2005). "3α-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period". Gynecological Endocrinology 21 (5): 268–279.  
  4. ^ Sheehan PM, Rice GE, Moses EK, Brennecke SP (2005). "5 Beta-dihydroprogesterone and steroid 5 beta-reductase decrease in association with human parturition at term". Mol. Hum. Reprod. 11 (7): 495–501.  
  5. ^ a b Ocvirk, Rok; Pearson Murphy, Beverley E.; Franklin, Keith B.J.; Abbott, Frances V. (2008). "Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test". Pain 138 (2): 402–409.  
  6. ^ Morris KD, Moorefield CN, Amin J (1999). "Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids". Mol. Pharmacol. 56 (4): 752–9.  
  7. ^ Leb, Colette R.; Hu, Fen-Yun; Pearson Murphy, Beverley E. (1997). "Metabolism of Progesterone by Human Lymphocytes: Production of Neuroactive Steroids1". The Journal of Clinical Endocrinology & Metabolism 82 (12): 4064–4068.  
  8. ^ Rodgers, R (1998). "Behaviorally Selective Effects of Neuroactive Steroids on Plus-Maze Anxiety in Mice". Pharmacology Biochemistry and Behavior 59 (1): 221–232.  
  9. ^ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998). "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". J. Clin. Invest. 102 (5): 1016–23.  
  10. ^ Hagedorn, K. A.; Cooke, C.-L.; Falck, J. R.; Mitchell, B. F.; Davidge, S. T. (2006). "Regulation of Vascular Tone During Pregnancy: A Novel Role for the Pregnane X Receptor". Hypertension 49 (2): 328–333.  
  11. ^ a b Mitchell, Bryan F.; Mitchell, Jana M.; Chowdhury, Jeeshan; Tougas, Michelle; Engelen, Sanne M.E.; Senff, Nancy; Heijnen, Iris; Moore, John T.; Goodwin, Bryan; Wong, Susan; Davidge, Sandra T. (2005). "Metabolites of progesterone and the pregnane X receptor: A novel pathway regulating uterine contractility in pregnancy?". American Journal of Obstetrics and Gynecology 192 (4): 1304–1313.  
  12. ^ Lima-Hernández, Francisco J.; Beyer, Carlos; Gómora-Arrati, Porfirio; García-Juárez, Marcos; Encarnación-Sánchez, José L.; Etgen, Anne M.; González-Flores, Oscar (2012). "Src kinase signaling mediates estrous behavior induced by 5β-reduced progestins, GnRH, prostaglandin E2 and vaginocervical stimulation in estrogen-primed rats". Hormones and Behavior 62 (5): 579–584.  
  13. ^ Alexandros Makriyannis; Diane Biegel (4 November 2003). Drug Discovery Strategies and Methods. CRC Press. pp. 190–.  
  14. ^ a b Creasy, Robert K.; Resnik, Robert; Iams, Jay D.; Lockwood, Charles J.; Greene, Michael F.; Moore, Thomas R. (2013). Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. Elsevier Health Sciences. pp. 72–.  
  15. ^ Knobil and Neill's Physiology of Reproduction. Academic Press. 12 December 2005. pp. 2952–.