Neurosteroids are 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
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 Androsterone: 5α-androstan-3α-ol-17-one – GABAA receptor positive allosteric modulator Etiocholanolone: 5β-androstan-3α-ol-17-one – GABAA receptor positive allosteric modulator 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 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 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 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 SGE-872 – GABAA receptor positive allosteric modulator 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 The following are proneurosteroids:
EIDD-1723 – of EIDD-036 (see above) P1-185 – of progesterone and by extension pregnanediones, pregnanolones, and pregnanediols (see above) Progesterone carboxymethyloxime (P4-3-CMO) – of progesterone and by extension pregnanediones, pregnanolones, and pregnanediols (see above)
Excitatory
Natural
Cholestanes Cerebrosterol (24(S)-Hydroxycholesterol): cholest-5-en-3β,24S-diol – NMDA receptor positive allosteric modulator
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 SAGE-301 - oxysterol/cholesterol analogue – NMDA receptor positive allosteric modulator SAGE-718: oxysterol/cholesterol analogue; exact chemical structure undisclosed – NMDA receptor positive allosteric modulator
Mixed
Natural
Cholestanes Cholesterol: cholest-5-en-3β-ol – NMDA receptor positive allosteric modulator, possible GABAA receptor positive allosteric modulator, many other actions
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
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
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