List of neurosteroids

Allopregnanolone, a major endogenous inhibitory neurosteroid.

Steroid ring system.

This is a list of neurosteroids, or natural and synthetic steroids that are active on the mammalian nervous system through receptors other than steroid hormone receptors. It includes inhibitory, excitatory, and neurotrophic neurosteroids as well as pheromones and vomeropherines. In contrast to steroid hormones, neurosteroids have rapid, non-genomic effects through interactions with membrane steroid receptors and can quickly influence central nervous system function.

Inhibitory

Natural

Cholestanes

• 25-Hydroxycholesterol: cholest-5-en-3β,25-diol – NMDA receptor negative allosteric modulator ^[1]

Androstanes

• 3α,5α-Androstanediol (3α-androstanediol): 5α-androstane-3α,17β-diol – GABA_A receptor positive allosteric modulator
• 3α,5β-Androstanediol (etiocholanediol): 5β-androstane-3α,17β-diol – GABA_A receptor positive allosteric modulator
• 3α-Androstenol: 5α-androst-16-en-3α-ol – GABA_A receptor positive allosteric modulator ^[2]
• Androsterone: 5α-androstan-3α-ol-17-one – GABA_A receptor positive allosteric modulator ^[3]
• Etiocholanolone: 5β-androstan-3α-ol-17-one – GABA_A receptor positive allosteric modulator ^[3]

The following are proneurosteroids:

• Dihydrotestosterone (DHT; androstanolone, stanolone): 5α-androst-17β-ol-3-one – of the above-listed inhibitory androstane neurosteroids
• Testosterone: androst-4-en-17β-ol-3-one – of the above-listed inhibitory androstane neurosteroids

Pregnanes

• 3α-Dihydroprogesterone (3α-DHP): pregn-4-en-3α-ol-20-one – GABA_A receptor positive allosteric modulator
• 5α-Dihydroprogesterone (5α-DHP; allopregnanedione): 5α-pregnane-3,20-dione – GABA_A receptor positive allosteric modulator
• 5β-Dihydroprogesterone (5β-DHP; pregnanedione): 5β-pregnane-3,20-dione – GABA_A receptor positive allosteric modulator
• Allopregnanediol: 5α-pregnane-3α,20α-diol – GABA_A receptor positive allosteric modulator ^[4]
• Allopregnanolone (brexanolone; SAGE-547): 5α-pregnan-3α-ol-20-one – GABA_A receptor positive allosteric modulator
• Dihydrodeoxycorticosterone (DHDOC): 21-hydroxy-5α-pregnan-20-one – GABA_A receptor positive allosteric modulator
• Pregnanediol: 5β-pregnan-3α,20α-diol – GABA_A receptor positive allosteric modulator ^[4]
• Pregnanolone (eltanolone): 5β-pregnan-3α-ol-20-one – GABA_A receptor positive allosteric modulator
• Tetrahydrodeoxycorticosterone (THDOC): 3α,21-dihydroxy-5α-pregnan-20-one – GABA_A receptor positive allosteric modulator

The following are proneurosteroids:

• Deoxycorticosterone (desoxycortone): 21-hydroxypregn-4-ene-3,20-dione – of DHDOC and THDOC
• Pregnenolone (P5): pregn-5-en-3β-ol-20-one – of pregnanolones and pregnanediols (see above)
• Progesterone (P4): pregn-4-ene-3,20-dione – of pregnanediones, pregnanolones, and pregnanediols (see above)

Synthetic

Cholestanes

• Acebrochol (cholesteryl acetate dibromide): 5α,6β-dibromocholestan-3β-ol 3β-acetate – GABA_A receptor positive allosteric modulator

Pregnanes

• Alfadolone: 3α,21-dihydroxy-5α-pregnane-11,20-dione – GABA_A receptor positive allosteric modulator
• Alfadolone acetate: 3α,21-dihydroxy-5α-pregnane-11,20-dione 21-acetate – GABA_A receptor positive allosteric modulator
• Alfaxalone: 3α-hydroxy-5α-pregnane-11,20-dione – GABA_A receptor positive allosteric modulator
• EIDD-036 (P4-20-O): 20-(hydroxyimino)pregn-4-en-3-one – progesterone-like inhibitory neurosteroid ^[5]
• Ganaxolone: 3β-methyl-5α-pregnan-3α-ol-20-one – GABA_A receptor positive allosteric modulator
• Hydroxydione: 21-hydroxy-5β-pregnane-3,20-dione – GABA_A receptor positive allosteric modulator
• Minaxolone: 11α-(dimethylamino)-2β-ethoxy-5α-pregnan-3α-ol-20-one – GABA_A receptor positive allosteric modulator
• ORG-20599: 21-chloro-2β-morpholin-4-yl-5β-pregnan-3α-ol-20-one – GABA_A receptor positive allosteric modulator
• ORG-21465: 2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate – GABA_A receptor positive allosteric modulator
• Posovolone (Co 134444): 3β-Hydroxy-21-(1H-imidazol-1-yl)-3α-(methoxymethyl)-5α-pregnan-20-one – GABA_A receptor positive allosteric modulator
• Renanolone: 5β-pregnan-3α-ol-11,20-dione – GABA_A receptor positive allosteric modulator
• SGE-516 – GABA_A receptor positive allosteric modulator ^[6]
• SGE-872 – GABA_A receptor positive allosteric modulator ^[6]
• Zuranolone (SAGE-217): 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one – GABA_A receptor positive allosteric modulator ^{[7] [6]}

The following are proneurosteroids:

• EIDD-1723 – of EIDD-036 (see above) ^[5]
• P1-185 – of progesterone and by extension pregnanediones, pregnanolones, and pregnanediols (see above) ^{[8] [9]}
• Progesterone carboxymethyloxime (P4-3-CMO) – of progesterone and by extension pregnanediones, pregnanolones, and pregnanediols (see above) ^{[10] [11]}

Excitatory

Natural

Cholestanes

• Cerebrosterol (24(S)-Hydroxycholesterol): cholest-5-en-3β,24S-diol – NMDA receptor positive allosteric modulator ^[12]

Pregnanes

• 3β-Dihydroprogesterone (3β-DHP): pregn-4-en-3β-ol-20-one – GABA_A receptor negative allosteric modulator
• Epipregnanolone: 5β-pregnan-3β-ol-20-one – GABA_A receptor negative allosteric modulator
• Isopregnanolone (sepranolone): 5α-pregnan-3β-ol-20-one – GABA_A receptor negative allosteric modulator
• Pregnenolone sulfate (PS): pregn-5-en-3β-ol-20-one 3β-sulfate – GABA_A receptor negative allosteric modulator, NMDA receptor positive allosteric modulator, sigma-1 receptor agonist, TRPM3 agonist, other actions

The following are proneurosteroids:

• Pregnenolone (P5): pregn-5-en-3β-ol-20-one – of pregnenolone sulfate

Androstanes

• Dehydroepiandrosterone (DHEA; prasterone): androst-5-en-3β-ol-17-one – GABA_A receptor positive allosteric modulator, NMDA receptor positive allosteric modulator, sigma-1 receptor agonist, other actions
• Dehydroepiandrosterone sulfate (DHEA-S; prasterone sulfate): androst-5-en-3β-ol-17-one 3β-sulfate – GABA_A receptor negative allosteric modulator, NMDA receptor positive allosteric modulator, other actions

Synthetic

Androstanes

• 17-Phenylandrostenol (17-PA): 17-phenyl-5α-androst-16-en-3α-ol – GABA_A receptor negative allosteric modulator
• Golexanolone (GR-3027): 3α-ethynyl-3β-hydroxyandrostan-17E-one oxime – GABA_A receptor negative allosteric modulator

Others

• SAGE-201 - oxysterol/cholesterol analogue – NMDA receptor positive allosteric modulator ^[6]
• SAGE-301 - oxysterol/cholesterol analogue – NMDA receptor positive allosteric modulator ^[6]
• SAGE-718: oxysterol/cholesterol analogue; exact chemical structure undisclosed – NMDA receptor positive allosteric modulator ^[6]

Mixed

Natural

Cholestanes

• Cholesterol: cholest-5-en-3β-ol – NMDA receptor positive allosteric modulator, possible GABA_A receptor positive allosteric modulator, many other actions ^{[13] [14] [15]}

Pregnanes

• Epipregnanolone sulfate: 5β-pregnan-3β-ol-20-one 3β-sulfate – GABA_A and NMDA receptor negative allosteric modulator, TRPM3 agonist

Neurotrophic

Natural

Androstanes

• Dehydroepiandrosterone (DHEA; prasterone): androst-5-en-3β-ol-17-one – TrkA, TrkC, and p75^NTR agonist, TrkB ligand
• Dehydroepiandrosterone sulfate (DHEA-S; prasterone sulfate): androst-5-en-3β-ol-17-one 3β-sulfate – TrkA and p75^NTR agonist

Ergostanes

• Anicequol (NGA0187, NGD-187): 16β-acetoxy-3β,7β,11β-trihydroxy-5α-ergost-22(E)-en-6-one – non-endogenous; fungi-derived; undefined mechanism of action; shows neurotrophic activity in vitro; was formerly under development for the treatment of cognitive disorders ^[16]

Synthetic

Androstanes

• BNN-20: 17β-spiro-(androst-5-en-17,2'-oxiran)-3β-ol – TrkA, TrkB, and p75^NTR agonist

Pregnanes

• BNN-27: 17α,20R-epoxypregn-5-ene-3β,21-diol – TrkA and p75^NTR agonist

Antineurotrophic

Natural

Androstanes

• Testosterone: androst-4-en-17β-ol-3-one – TrkA and p75^NTR antagonist

Synthetic

Pregnanes

• Dexamethasone: 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione – TrkA and p75^NTR antagonist

Pheromones and pherines

See also: Pheromone § Humans, Sex pheromone § In_humans, and Pherine

Natural

Androstanes

• 3α-Androstenol: 5α-androst-16-en-3α-ol
• 3β-Androstenol: 5α-androst-16-en-3β-ol
• Androstadienol: androsta-5,16-dien-3β-ol
• Androstadienone: androsta-4,16-dien-3-one
• Androstenone: 5α-androst-16-en-3-one
• Androsterone: 5α-androstan-3α-ol-17-one

Estranes

• Estratetraenol: estra-1,3,5(10),16-tetraen-3-ol

Synthetic

Androstanes

• Fasedienol (Aloradine; PH94B; 4-androstadienol): androsta-4,16-dien-3β-ol

Estranes

• Estratetraenyl acetate (ETA): estra-1,3,5(10),16-tetraen-3-yl acetate

Pregnanes

• Pregnadienedione (PDD): pregna-4,20-dien-3,6-dione

Others

• PH10, PH15, PH30, PH56, PH78, PH84, Salubrin (PH80) – pherines with undefined structures developed by a company called Pherin Pharmaceuticals

Others

Natural

Pregnanes

• Pregnenolone (P5): pregn-5-en-3β-ol-20-one – MAP2 ligand
• Progesterone (P4): pregn-4-ene-3,20-dione – sigma-1 receptor antagonist, nicotinic acetylcholine receptor negative allosteric modulator, MAP2 ligand, other actions

Spirostanes

See also: spiro compound, diosgenin, and caproate

• Caprospinol (SP-233; diosgenin 3-caproate): (22R,25R)-20α-spirost-5-en-3β-yl hexanoate – β-amyloid ligand, sigma-1 receptor ligand, other actions; found naturally in Gynura japonica ; under development as a neuroprotective against Alzheimer's disease ^{[17] [18]}

Estranes

• Estradiol (E2): Estra-1,3,5(10)-triene-3,17β-diol; found to increase the expression of the oxytocin receptor.

Synthetic

Pregnanes

• 3β-Methoxypregnenolone (MAP-4343): 3β-methoxypregn-5-en-20-one – MAP2 ligand
• Cyclopregnol (neurosterone): 6β-hydroxy-3:5-cyclopregnan-20-one – undefined mechanism of action; developed as a "psychotropic agent" for the treatment of "mental disorders" such as schizophrenia in the 1950s

Androstanes

• Cetadiol: androst-5-ene-3β,16α-diol – undefined mechanism of action; developed as a "tranquilizer" and for the treatment of alcoholism in the 1950s

See also

• List of steroids
• Neurosteroidogenesis inhibitor

References

1. Linsenbardt AJ, Taylor A, Emnett CM, Doherty JJ, Krishnan K, Covey DF, Paul SM, Zorumski CF, Mennerick S (2014). "Different oxysterols have opposing actions at N-methyl-D-aspartate receptors". Neuropharmacology. 85: 232–42. doi:10.1016/j.neuropharm.2014.05.027. PMC   4107067 . PMID   24878244.
2. Kaminski RM, Marini H, Ortinski PI, Vicini S, Rogawski MA (2006). "The pheromone androstenol (5 alpha-androst-16-en-3 alpha-ol) is a neurosteroid positive modulator of GABAA receptors". J. Pharmacol. Exp. Ther. 317 (2): 694–703. doi:10.1124/jpet.105.098319. PMID   16415088. S2CID   95393004.
3. Kaminski RM, Marini H, Kim WJ, Rogawski MA (2005). "Anticonvulsant activity of androsterone and etiocholanolone". Epilepsia. 46 (6): 819–27. doi:10.1111/j.1528-1167.2005.00705.x. PMC   1181535 . PMID   15946323.
4. Belelli D, Lambert JJ, Peters JA, Gee KW, Lan NC (1996). "Modulation of human recombinant GABAA receptors by pregnanediols". Neuropharmacology. 35 (9–10): 1223–31. doi:10.1016/s0028-3908(96)00066-4. PMID   9014137. S2CID   10437944.
5. Wali B, Sayeed I, Guthrie DB, Natchus MG, Turan N, Liotta DC, Stein DG (October 2016). "Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats". Neuropharmacology. 109: 148–158. doi:10.1016/j.neuropharm.2016.05.017. PMID   27267687. S2CID   19906601.
6. Blanco MJ, La D, Coughlin Q, Newman CA, Griffin AM, Harrison BL, Salituro FG (2018). "Breakthroughs in neuroactive steroid drug discovery". Bioorg. Med. Chem. Lett. 28 (2): 61–70. doi:10.1016/j.bmcl.2017.11.043. PMID   29223589.
7. Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, Belfort GM, Dai J, Loya CM, Ackley MA, Althaus AL, Grossman SJ, Hoffmann E, Doherty JJ, Robichaud AJ (2017). "Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor". J. Med. Chem. 60 (18): 7810–7819. doi:10.1021/acs.jmedchem.7b00846. PMID   28753313.
8. MacNevin CJ, Atif F, Sayeed I, Stein DG, Liotta DC (2009). "Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury". J. Med. Chem. 52 (19): 6012–23. doi:10.1021/jm900712n. PMID   19791804.
9. Guthrie DB, Stein DG, Liotta DC, Lockwood MA, Sayeed I, Atif F, Arrendale RF, Reddy GP, Evers TJ, Marengo JR, Howard RB, Culver DG, Natchus MG (2012). "Water-soluble progesterone analogues are effective, injectable treatments in animal models of traumatic brain injury". ACS Med Chem Lett. 3 (5): 362–6. doi:10.1021/ml200303r. PMC   4025794 . PMID   24900479.
10. Basu, Krishnakali; Mitra, Ashim K. (1990). "Effects of 3-hydrazone modification on the metabolism and protein binding of progesterone". International Journal of Pharmaceutics. 65 (1–2): 109–114. doi:10.1016/0378-5173(90)90015-V. ISSN   0378-5173.
11. Basu, Krishnakali; Kildsig, Dane O.; Mitra, Ashim K. (1988). "Synthesis and kinetic stability studies of progesterone derivatives". International Journal of Pharmaceutics. 47 (1–3): 195–203. doi:10.1016/0378-5173(88)90231-1. ISSN   0378-5173.
12. Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, Crawford DC, Linsenbardt AJ, Shu HJ, Izumi Y, Mennerick SJ, Zorumski CF (2013). "The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors". J. Neurosci. 33 (44): 17290–300. doi:10.1523/JNEUROSCI.2619-13.2013. PMC   3812502 . PMID   24174662.
13. Hénin J, Salari R, Murlidaran S, Brannigan G (2014). "A predicted binding site for cholesterol on the GABAA receptor". Biophys. J. 106 (9): 1938–49. Bibcode:2014BpJ...106.1938H. doi:10.1016/j.bpj.2014.03.024. PMC   4017285 . PMID   24806926.
14. Levitan I, Singh DK, Rosenhouse-Dantsker A (2014). "Cholesterol binding to ion channels". Front Physiol. 5: 65. doi: 10.3389/fphys.2014.00065 . PMC   3935357 . PMID   24616704.
15. Lange Y, Steck TL (2016). "Active membrane cholesterol as a physiological effector". Chem. Phys. Lipids. 199: 74–93. doi:10.1016/j.chemphyslip.2016.02.003. PMID   26874289.
16. Nozawa Y, Sakai N, Matsumoto K, Mizoue K (2002). "A novel neuritogenic compound, NGA0187". J. Antibiot. 55 (7): 629–34. doi: 10.7164/antibiotics.55.629 . PMID   12243452.
17. Papadopoulos V, Lecanu L (2012). "Caprospinol: discovery of a steroid drug candidate to treat Alzheimer's disease based on 22R-hydroxycholesterol structure and properties". J. Neuroendocrinol. 24 (1): 93–101. doi:10.1111/j.1365-2826.2011.02167.x. PMID   21623958. S2CID   24032303.
18. "Research programme: Neurodegenerative disorders therapeutics - Samaritan/McGill University - AdisInsight".