List of neurosteroids
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
[edit]Natural
[edit]Cholestanes
[edit]- 25-Hydroxycholesterol: cholest-5-en-3β,25-diol – NMDA receptor negative allosteric modulator[1]
Androstanes
[edit]- 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
[edit]- 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
[edit]Cholestanes
[edit]- Acebrochol (cholesteryl acetate dibromide): 5α,6β-dibromocholestan-3β-ol 3β-acetate – GABAA receptor positive allosteric modulator
Pregnanes
[edit]- 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
[edit]Natural
[edit]Cholestanes
[edit]- Cerebrosterol (24(S)-Hydroxycholesterol): cholest-5-en-3β,24S-diol – NMDA receptor positive allosteric modulator[12]
Pregnanes
[edit]- 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
[edit]- 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
[edit]Androstanes
[edit]- 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
[edit]- 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
[edit]Natural
[edit]Cholestanes
[edit]- Cholesterol: cholest-5-en-3β-ol – NMDA receptor positive allosteric modulator, possible GABAA receptor positive allosteric modulator, many other actions[13][14][15]
Pregnanes
[edit]- Epipregnanolone sulfate: 5β-pregnan-3β-ol-20-one 3β-sulfate – GABAA and NMDA receptor negative allosteric modulator, TRPM3 agonist
Neurotrophic
[edit]Natural
[edit]Androstanes
[edit]- 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
[edit]- 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
[edit]Androstanes
[edit]- BNN-20: 17β-spiro-(androst-5-en-17,2'-oxiran)-3β-ol – TrkA, TrkB, and p75NTR agonist
Pregnanes
[edit]- BNN-27: 17α,20R-epoxypregn-5-ene-3β,21-diol – TrkA and p75NTR agonist
Antineurotrophic
[edit]Natural
[edit]Androstanes
[edit]- Testosterone: androst-4-en-17β-ol-3-one – TrkA and p75NTR antagonist
Synthetic
[edit]Pregnanes
[edit]- Dexamethasone: 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione – TrkA and p75NTR antagonist
Pheromones and pherines
[edit]Natural
[edit]Androstanes
[edit]- 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
[edit]- Estratetraenol: estra-1,3,5(10),16-tetraen-3-ol
Synthetic
[edit]Androstanes
[edit]- Fasedienol (Aloradine; PH94B; 4-androstadienol): androsta-4,16-dien-3β-ol
Estranes
[edit]- Estratetraenyl acetate (ETA): estra-1,3,5(10),16-tetraen-3-yl acetate
Pregnanes
[edit]- Pregnadienedione (PDD): pregna-4,20-dien-3,6-dione
Others
[edit]- PH10, PH15, PH30, PH56, PH78, PH84, Salubrin (PH80) – pherines with undefined structures developed by a company called Pherin Pharmaceuticals
Others
[edit]Natural
[edit]Pregnanes
[edit]- 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
[edit]- 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
[edit]- Estradiol (E2): Estra-1,3,5(10)-triene-3,17β-diol; found to increase the expression of the oxytocin receptor.
Synthetic
[edit]Pregnanes
[edit]- 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
[edit]- 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
[edit]References
[edit]- ^ 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.
- ^ 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.
- ^ a b 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.
- ^ a b 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.
- ^ a b 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.
- ^ a b c d e f 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "Research programme: Neurodegenerative disorders therapeutics - Samaritan/McGill University - AdisInsight".