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3α-Androstanediol

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3α-Androstanediol
Names
IUPAC name
5α-Androstane-3α,17β-diol
Systematic IUPAC name
(1S,3aS,3bR,5aS,7R,9aS,9bS,11aS)-9a,11a-Dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-1,7-diol
Other names
Hombreol
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.015.862 Edit this at Wikidata
UNII
  • InChI=1S/C19H32O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h12-17,20-21H,3-11H2,1-2H3/t12-,13+,14-,15-,16-,17-,18-,19-/m0/s1
    Key: CBMYJHIOYJEBSB-KHOSGYARSA-N
  • InChI=1/C19H32O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h12-17,20-21H,3-11H2,1-2H3/t12-,13+,14-,15-,16-,17-,18-,19-/m0/s1
    Key: CBMYJHIOYJEBSB-KHOSGYARBM
  • C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Properties
C19H32O2
Molar mass 292.463 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

3α-Androstanediol also known as 5α-androstane-3α,17β-diol and sometimes shortened in the literature to 3α-diol, is an endogenous steroid hormone and neurosteroid and a metabolite of androgens like dihydrotestosterone (DHT).[1][2][3]

Biological activity

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3α-Androstanediol is an inhibitory androstane neurosteroid and weak androgen and estrogen.[1][2][3]

As a neurosteroid, it acts as a potent positive allosteric modulator of the GABAA receptor,[4] and has been found to have rewarding,[5][6] anxiolytic,[7] pro-sexual,[8] and anticonvulsant effects.[9][10] As androgens such as testosterone and DHT are known to have many of the same effects as 3α-diol and are converted into it in vivo, it is thought that this compound may in part be responsible for said effects.[5][6][7][10]

Relative to its isomer 3β-androstanediol, which is a potent estrogen, 3α-androstanediol has substantially lower, though still significant affinity for the estrogen receptors, with a several-fold preference for ERβ over ERα.[11][12] It has approximately 0.07% and 0.3% of the affinity of estradiol at the ERα and ERβ, respectively.[13]

Biochemistry

[edit]
Testosterone metabolism in humans
Testosterone structures
The image above contains clickable links
This diagram illustrates the metabolic pathways involved in the metabolism of DHT in humans. In addition to the transformations shown in the diagram, conjugation (e.g., sulfation and glucuronidation) occurs with DHT and metabolites that have one or more available hydroxyl (–OH) groups.

3α-Androstanediol shows high affinity for sex hormone-binding globulin (SHBG), similar to that of testosterone.[14]

Chemistry

[edit]
See also: List of neurosteroids

3α-Androstanediol, also known as 5α-androstane-3α,17β-diol, is a naturally occurring androstane steroid and a structural analogue of DHT (5α-androstan-17β-ol-3-one). A notable positional isomer of 3α-androstanediol is 3β-androstanediol.

An orally active synthetic analogue of 3α-androstanediol, 17α-ethynyl-3α-androstanediol (HE-3235, Apoptone), was formerly under investigation for the treatment of prostate cancer and breast cancer.[15]

References

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  1. ^ a b Reddy DS (2010). "Neurosteroids". Sex Differences in the Human Brain, their Underpinnings and Implications. Progress in Brain Research. Vol. 186. pp. 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. ISBN 9780444536303. PMC 3139029. PMID 21094889.
  2. ^ a b Jin Y, Penning TM (March 2001). "Steroid 5alpha-reductases and 3alpha-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism". Best Pract. Res. Clin. Endocrinol. Metab. 15 (1): 79–94. doi:10.1053/beem.2001.0120. PMID 11469812.
  3. ^ a b Penning TM, Bauman DR, Jin Y, Rizner TL (February 2007). "Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor". Mol. Cell. Endocrinol. 265–266: 77–82. doi:10.1016/j.mce.2006.12.007. PMC 1857325. PMID 17223255.
  4. ^ Reddy DS, Jian K (September 2010). "The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors". J. Pharmacol. Exp. Ther. 334 (3): 1031–41. doi:10.1124/jpet.110.169854. PMC 2939675. PMID 20551294.
  5. ^ a b Frye CA (February 2007). "Some rewarding effects of androgens may be mediated by actions of its 5alpha-reduced metabolite 3alpha-androstanediol". Pharmacol. Biochem. Behav. 86 (2): 354–67. doi:10.1016/j.pbb.2006.10.003. PMC 1857333. PMID 17112575.
  6. ^ a b Rosellini RA, Svare BB, Rhodes ME, Frye CA (November 2001). "The testosterone metabolite and neurosteroid 3alpha-androstanediol may mediate the effects of testosterone on conditioned place preference". Brain Res. Brain Res. Rev. 37 (1–3): 162–71. doi:10.1016/s0165-0173(01)00116-3. PMID 11744084. S2CID 44735355.
  7. ^ a b Fernández-Guasti A, Martínez-Mota L (September 2005). "Anxiolytic-like actions of testosterone in the burying behavior test: role of androgen and GABA-benzodiazepine receptors". Psychoneuroendocrinology. 30 (8): 762–70. doi:10.1016/j.psyneuen.2005.03.006. PMID 15919582. S2CID 3150411.
  8. ^ Sánchez Montoya EL, Hernández L, Barreto-Estrada JL, Ortiz JG, Jorge JC (November 2010). "The testosterone metabolite 3α-diol enhances female rat sexual motivation when infused in the nucleus accumbens shell". J Sex Med. 7 (11): 3598–609. doi:10.1111/j.1743-6109.2010.01937.x. PMC 4360968. PMID 20646182.
  9. ^ Reddy DS (March 2004). "Anticonvulsant activity of the testosterone-derived neurosteroid 3alpha-androstanediol". NeuroReport. 15 (3): 515–8. doi:10.1097/00001756-200403010-00026. PMID 15094514. S2CID 29967602.
  10. ^ a b Reddy DS (2004). "Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3alpha-androstanediol and 17beta-estradiol". Neuroscience. 129 (1): 195–207. doi:10.1016/j.neuroscience.2004.08.002. PMID 15489042. S2CID 54391883.
  11. ^ Baker ME (2002). "Recent insights into the origins of adrenal and sex steroid receptors" (PDF). J. Mol. Endocrinol. 28 (3): 149–52. doi:10.1677/jme.0.0280149. PMID 12063181.
  12. ^ Kuiper, George G. J. M.; Carlsson, Bo; Grandien, Kaj; Enmark, Eva; Häggblad, Johan; Nilsson, Stefan; Gustafsson, Jan-Åke (1997). "Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors α and β". Endocrinology. 138 (3): 863–870. doi:10.1210/endo.138.3.4979. ISSN 0013-7227. PMID 9048584.
  13. ^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi:10.1210/endo.138.3.4979. PMID 9048584.
  14. ^ Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W (February 2015). "Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein". Toxicol. Sci. 143 (2): 333–48. doi:10.1093/toxsci/kfu231. PMID 25349334.
  15. ^ Ahlem C, Kennedy M, Page T, Bell D, Delorme E, Villegas S, Reading C, White S, Stickney D, Frincke J (2012). "17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism". Invest New Drugs. 30 (1): 59–78. doi:10.1007/s10637-010-9517-0. PMID 20814732. S2CID 24785562.


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