Chemistry:List of neurosteroids
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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 – GABAA receptor positive allosteric modulator
- 3α,5β-Androstanediol (etiocholanediol): 5β-androstane-3α,17β-diol – GABAA receptor positive allosteric modulator
- 3α-Androstenol: 5α-androst-16-en-3α-ol – GABAA receptor positive allosteric modulator[2]
- Androsterone: 5α-androstan-3α-ol-17-one – GABAA receptor positive allosteric modulator[3]
- Etiocholanolone: 5β-androstan-3α-ol-17-one – GABAA 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 – GABAA receptor positive allosteric modulator
- 5α-Dihydroprogesterone (5α-DHP; allopregnanedione): 5α-pregnane-3,20-dione – GABAA receptor positive allosteric modulator
- 5β-Dihydroprogesterone (5β-DHP; pregnanedione): 5β-pregnane-3,20-dione – GABAA receptor positive allosteric modulator
- Allopregnanediol: 5α-pregnane-3α,20α-diol – GABAA receptor positive allosteric modulator[4]
- Allopregnanolone (brexanolone; SAGE-547): 5α-pregnan-3α-ol-20-one – GABAA receptor positive allosteric modulator
- Dihydrodeoxycorticosterone (DHDOC): 21-hydroxy-5α-pregnan-20-one – GABAA receptor positive allosteric modulator
- Pregnanediol: 5β-pregnan-3α,20α-diol – GABAA receptor positive allosteric modulator[4]
- Pregnanolone (eltanolone): 5β-pregnan-3α-ol-20-one – GABAA receptor positive allosteric modulator
- Tetrahydrodeoxycorticosterone (THDOC): 3α,21-dihydroxy-5α-pregnan-20-one – GABAA 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 – GABAA receptor positive allosteric modulator
Pregnanes
- Alfadolone: 3α,21-dihydroxy-5α-pregnane-11,20-dione – GABAA receptor positive allosteric modulator
- Alfadolone acetate: 3α,21-dihydroxy-5α-pregnane-11,20-dione 21-acetate – GABAA receptor positive allosteric modulator
- Alfaxalone: 3α-hydroxy-5α-pregnane-11,20-dione – GABAA 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 – GABAA receptor positive allosteric modulator
- Hydroxydione: 21-hydroxy-5β-pregnane-3,20-dione – GABAA receptor positive allosteric modulator
- Minaxolone: 11α-(dimethylamino)-2β-ethoxy-5α-pregnan-3α-ol-20-one – GABAA receptor positive allosteric modulator
- ORG-20599: 21-chloro-2β-morpholin-4-yl-5β-pregnan-3α-ol-20-one – GABAA receptor positive allosteric modulator
- ORG-21465: 2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate – GABAA receptor positive allosteric modulator
- Posovolone (Co 134444): 3β-Hydroxy-21-(1H-imidazol-1-yl)-3α-(methoxymethyl)-5α-pregnan-20-one – GABAA receptor positive allosteric modulator
- Renanolone: 5β-pregnan-3α-ol-11,20-dione – GABAA receptor positive allosteric modulator
- SGE-516 – GABAA receptor positive allosteric modulator[6]
- SGE-872 – GABAA 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 – GABAA 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 – GABAA receptor negative allosteric modulator
- Epipregnanolone: 5β-pregnan-3β-ol-20-one – GABAA receptor negative allosteric modulator
- Isopregnanolone (sepranolone): 5α-pregnan-3β-ol-20-one – GABAA receptor negative allosteric modulator
- Pregnenolone sulfate (PS): pregn-5-en-3β-ol-20-one 3β-sulfate – GABAA 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 – GABAA 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 – GABAA 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 – GABAA receptor negative allosteric modulator
- Golexanolone (GR-3027): 3α-ethynyl-3β-hydroxyandrostan-17E-one oxime – GABAA 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 GABAA receptor positive allosteric modulator, many other actions[13][14][15]
Pregnanes
- Epipregnanolone sulfate: 5β-pregnan-3β-ol-20-one 3β-sulfate – GABAA and NMDA receptor negative allosteric modulator, TRPM3 agonist
Neurotrophic
Natural
Androstanes
- Dehydroepiandrosterone (DHEA; prasterone): androst-5-en-3β-ol-17-one – TrkA, TrkC, and p75NTR agonist, TrkB ligand
- Dehydroepiandrosterone sulfate (DHEA-S; prasterone sulfate): androst-5-en-3β-ol-17-one 3β-sulfate – TrkA and p75NTR 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 p75NTR agonist
Pregnanes
- BNN-27: 17α,20R-epoxypregn-5-ene-3β,21-diol – TrkA and p75NTR agonist
Antineurotrophic
Natural
Androstanes
- Testosterone: androst-4-en-17β-ol-3-one – TrkA and p75NTR antagonist
Synthetic
Pregnanes
- Dexamethasone: 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione – TrkA and p75NTR antagonist
Pheromones and pherines
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
- 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
References
- ↑ "Different oxysterols have opposing actions at N-methyl-D-aspartate receptors". Neuropharmacology 85: 232–42. 2014. doi:10.1016/j.neuropharm.2014.05.027. PMID 24878244.
- ↑ "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. 2006. doi:10.1124/jpet.105.098319. PMID 16415088.
- ↑ 3.0 3.1 "Anticonvulsant activity of androsterone and etiocholanolone". Epilepsia 46 (6): 819–27. 2005. doi:10.1111/j.1528-1167.2005.00705.x. PMID 15946323.
- ↑ 4.0 4.1 "Modulation of human recombinant GABAA receptors by pregnanediols". Neuropharmacology 35 (9–10): 1223–31. 1996. doi:10.1016/s0028-3908(96)00066-4. PMID 9014137.
- ↑ 5.0 5.1 "Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats". Neuropharmacology 109: 148–158. October 2016. doi:10.1016/j.neuropharm.2016.05.017. PMID 27267687.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Breakthroughs in neuroactive steroid drug discovery". Bioorg. Med. Chem. Lett. 28 (2): 61–70. 2018. doi:10.1016/j.bmcl.2017.11.043. PMID 29223589.
- ↑ "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. 2017. doi:10.1021/acs.jmedchem.7b00846. PMID 28753313.
- ↑ "Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury". J. Med. Chem. 52 (19): 6012–23. 2009. doi:10.1021/jm900712n. PMID 19791804.
- ↑ "Water-soluble progesterone analogues are effective, injectable treatments in animal models of traumatic brain injury". ACS Med Chem Lett 3 (5): 362–6. 2012. doi:10.1021/ml200303r. PMID 24900479.
- ↑ 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.
- ↑ 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.
- ↑ "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. 2013. doi:10.1523/JNEUROSCI.2619-13.2013. PMID 24174662.
- ↑ "A predicted binding site for cholesterol on the GABAA receptor". Biophys. J. 106 (9): 1938–49. 2014. doi:10.1016/j.bpj.2014.03.024. PMID 24806926. Bibcode: 2014BpJ...106.1938H.
- ↑ "Cholesterol binding to ion channels". Front Physiol 5: 65. 2014. doi:10.3389/fphys.2014.00065. PMID 24616704.
- ↑ "Active membrane cholesterol as a physiological effector". Chem. Phys. Lipids 199: 74–93. 2016. doi:10.1016/j.chemphyslip.2016.02.003. PMID 26874289.
- ↑ "A novel neuritogenic compound, NGA0187". J. Antibiot. 55 (7): 629–34. 2002. doi:10.7164/antibiotics.55.629. PMID 12243452.
- ↑ "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. 2012. doi:10.1111/j.1365-2826.2011.02167.x. PMID 21623958.
- ↑ "Research programme: Neurodegenerative disorders therapeutics - Samaritan/McGill University - AdisInsight". http://adisinsight.springer.com/drugs/800017449.
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