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Pregnenolone
Pregnenolone
(P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocorticoids. In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.[1]

Contents

1 Biological activity

1.1 Neurosteroid
Neurosteroid
activity

1.1.1 Microtubule-associated protein 2

1.2 Nuclear receptors

2 Biochemistry

2.1 Biosynthesis 2.2 Metabolism

3 Pharmacology 4 Chemistry

4.1 Derivatives

5 Society and culture

5.1 Brand names

6 References

Biological activity[edit] Neurosteroid
Neurosteroid
activity[edit] Pregnenolone
Pregnenolone
and its 3β-sulfate, pregnenolone sulfate, like DHEA, DHEA sulfate, and progesterone, belong to the group of neurosteroids that are found in high concentrations in certain areas of the brain, and are synthesized there. Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone
Pregnenolone
and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning.[2] Pregnenolone
Pregnenolone
is also being considered as a potential treatment for schizophrenia.[1] Although pregnenolone itself does not possess these activities, its metabolite pregnenolone sulfate is a negative allosteric modulator of the GABAA receptor[3] as well as a positive allosteric modulator of the NMDA receptor.[4][5] In addition, pregnenolone sulfate has been shown to activate the transient receptor potential M3 (TRPM3) ion channel in hepatocytes and pancreatic islets causing calcium entry and subsequent insulin release.[6] Pregnenolone
Pregnenolone
is involved in a natural negative feedback loop against CB1 receptor
CB1 receptor
activation in animals.[7] It prevents CB1 receptor agonists like tetrahydrocannabinol, the main active constituent in cannabis, from fully activating the CB1 [7] Microtubule-associated protein 2[edit] Pregnenolone
Pregnenolone
has been found to bind with high, nanomolar affinity to microtubule-associated protein 2 (MAP2) in the brain.[8][9] In contrast to pregnenolone, pregnenolone sulfate did not bind to microtubules.[8][9] However, progesterone did and with similar affinity to pregnenolone, although unlike pregnenolone, it did not increase binding of MAP2 to tubulin.[8][9] Pregnenolone
Pregnenolone
was found to induce tubule polymerization in neuronal cultures and to increase neurite growth in PC12 cells treated with nerve growth factor.[8][9] As such, pregnenolone may control formation and stabilization of microtubules in neurons and may affect both neural development during prenatal development and neural plasticity during aging.[8][9] The 3β-methyl ether of pregnenolone, 3β-methoxypregnenolone
3β-methoxypregnenolone
(MAP-4343), retains similar activity to pregnenolone in regards to interaction with MAP2,[8][9] and is under development for potential clinical use for indications such as the treatment of brain and spinal cord injury and depressive disorders.[10][11][12][13] Nuclear receptors[edit] Pregnenolone
Pregnenolone
has been found to act as an agonist of the pregnane X receptor.[14] Biochemistry[edit]

Steroidogenesis, showing pregnenolone near top left.

Biosynthesis[edit] Pregnenolone
Pregnenolone
is synthesized from cholesterol. This conversion involves hydroxylation of the side chain at the C20 and C22 positions, with cleavage of the side chain. The enzyme performing this task is cytochrome P450scc, located in the mitochondria, and controlled by anterior pituitary trophic hormones, such as adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone, in the adrenal glands and gonads. There are two intermediates in the transformation of cholesterol into pregnenolone, 22R-hydroxycholesterol
22R-hydroxycholesterol
and 20α,22R-dihydroxycholesterol, and all three steps in the transformation are catalyzed by P450scc. To assay conversion of cholesterol to pregnenolone, radiolabelled cholesterol has been used.[15] Pregnenolone
Pregnenolone
product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns.[15] Pregnenolone
Pregnenolone
is produced mainly in the gonads, adrenal glands, and the brain.[16] Metabolism[edit] Pregnenolone
Pregnenolone
undergoes further steroid metabolism in one of several ways:

Pregnenolone
Pregnenolone
can be converted into progesterone. The critical enzyme step is two-fold using a 3β-hydroxysteroid dehydrogenase
3β-hydroxysteroid dehydrogenase
and a Δ5-4 isomerase. The latter transfers the double bond from C5 to C4 on the A ring. Progesterone
Progesterone
is the entry into the Δ4 pathway, resulting in production of 17α-hydroxyprogesterone
17α-hydroxyprogesterone
and androstenedione, precursor to testosterone and estrone. Aldosterone
Aldosterone
and corticosteroids are also derived from progesterone or its derivatives. Pregnenolone
Pregnenolone
can be converted to 17α-hydroxypregnenolone
17α-hydroxypregnenolone
by the enzyme 17α-hydroxylase (CYP17A1). Using this pathway, termed Δ5 pathway, the next step is conversion to dehydroepiandrosterone (DHEA) via 17,20-lyase (CYP17A1). DHEA is the precursor of androstenedione. Pregnenolone
Pregnenolone
can be converted to androstadienol by 16-ene synthase (CYP17A1). Pregnenolone
Pregnenolone
can be converted to pregnenolone sulfate by steroid sulfotransferase, and this conversion can be reversed by steroid sulfatase.

Pharmacology[edit] Oral administration
Oral administration
of 50 or 100 mg pregnenolone has been found to have minimal or negligible effect on urinary levels of testosterone and testosterone metabolites, including of androsterone, etiocholanolone, 5β-androstanediol, androstadienol, and androstenol (and/or their conjugates), and this suggests that only a small amount of pregnenolone is converted into testosterone.[17][18] This is in accordance with findings on the conversion of DHEA into testosterone, in which only 1.5% of an oral dose of DHEA was found to be converted into testosterone.[17] In contrast to the androstanes, 50 or 100 mg oral pregnenolone has been found to significantly and in fact "strongly" increase urinary levels of the progesterone metabolites pregnanediol and pregnanolone (and/or their conjugates), whereas pregnanetriol was unaffected.[17][18] Unlike the case of oral administration, transdermal administration of 30 mg/day pregnenolone cream has not been found to affect urinary levels of metabolites of any other steroids, including of progesterone.[18] Sripada et al. reported that oral pregnenolone is preferentially metabolized into the neurosteroid allopregnanolone rather than into other steroids such as DHEA or cortisol.[19] In further research by their group, a single 400 mg dose of oral pregnenolone at 3 hours post-administration was found to result in a 3-fold elevation in serum levels of pregnenolone and a 7-fold increase in allopregnanolone levels.[19] Pregnanolone
Pregnanolone
levels increased by approximately 60% while DHEA levels decreased non-significantly by approximately 5% and cortisol levels were not affected.[19] Another study found that allopregnanolone levels were increased by 3-fold at 2 hours post-administration following a single 400 mg oral dose of pregnenolone.[19] In addition to allopregnanolone, exogenous pregnenolone also functions as a prohormone of pregnenolone sulfate.[20] Pregnenolone
Pregnenolone
is lipophilic and readily crosses the blood-brain-barrier.[19] Chemistry[edit] See also: List of neurosteroids Pregnenolone
Pregnenolone
is also known chemically as pregn-5-en-3β-ol-20-one. Like other steroids, it consists of four interconnected cyclic hydrocarbons. The compound contains ketone and hydroxyl functional groups, two methyl branches, and a double bond at C5, in the B cyclic hydrocarbon ring. Like many steroid hormones, it is hydrophobic. The sulfated derivative, pregnenolone sulfate, is water-soluble. 3β-Dihydroprogesterone
3β-Dihydroprogesterone
(pregn-4-en-3β-ol-20-one) is an isomer of pregnenolone in which the C5 double bond has been replaced with a C4 double bond. Derivatives[edit] A few synthetic ester derivatives of pregnenolone exist.[21] These include pregnenolone acetate (Antofin, Previsone, Pregno-Pan) and pregnenolone succinate (Panzalone, Formula 405).[21] Prebediolone acetate (Acetoxanon, Acetoxy-Prenolon, Artisone, Artivis, Pregnartrone, Sterosone), the 21-acetate ester of 21-hydroxypregnenolone, also exists.[21] These esters are all described as glucocorticoids similarly to pregnenolone.[21] Society and culture[edit] Brand names[edit] Pregnenolone
Pregnenolone
is or has been marketed as a pharmaceutical drug in some countries.[22] Brand names of pregnenolone have included Arthenolone, Bina-Skin, Enelone, Natolone, Pregnetan, Pregneton, Pregnolon, Prenolon, Regnosone, Sharmone, and Skinostelon.[21][22] It is described in the context of medical use as an "adrenal cortex hormone" or a glucocorticoid for the treatment of rheumatoid arthritis.[21][21] References[edit]

^ a b Marx CE, Bradford DW, Hamer RM, et al. (September 2011). " Pregnenolone
Pregnenolone
as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence". Neuroscience. 191: 78–90. doi:10.1016/j.neuroscience.2011.06.076. PMID 21756978.  ^ Vallée M, Mayo W, Le Moal M (November 2001). "Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging". Brain
Brain
Research. Brain
Brain
Research Reviews. 37 (1-3): 301–12. doi:10.1016/S0165-0173(01)00135-7. PMID 11744095.  ^ Majewska MD, Mienville JM, Vicini S (August 1988). "Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons". Neuroscience Letters. 90 (3): 279–84. doi:10.1016/0304-3940(88)90202-9. PMID 3138576.  ^ Wu FS, Gibbs TT, Farb DH (September 1991). " Pregnenolone
Pregnenolone
sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor". Molecular Pharmacology. 40 (3): 333–6. PMID 1654510.  ^ Irwin RP, Maragakis NJ, Rogawski MA, Purdy RH, Farb DH, Paul SM (July 1992). " Pregnenolone sulfate
Pregnenolone sulfate
augments NMDA receptor
NMDA receptor
mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons". Neurosci Lett. 141 (1): 30–4. doi:10.1016/0304-3940(92)90327-4. PMID 1387199.  ^ Wagner TF, Loch S, Lambert S, et al. (December 2008). "Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells". Nature Cell Biology. 10 (12): 1421–30. doi:10.1038/ncb1801. PMID 18978782.  ^ a b https://www.sciencedaily.com/releases/2014/01/140102142012.htm ^ a b c d e f Mellon SH (2007). " Neurosteroid
Neurosteroid
regulation of central nervous system development". Pharmacol. Ther. 116 (1): 107–24. doi:10.1016/j.pharmthera.2007.04.011. PMC 2386997 . PMID 17651807.  ^ a b c d e f Fontaine-Lenoir V, Chambraud B, Fellous A, David S, Duchossoy Y, Baulieu EE, Robel P (2006). "Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor". Proc. Natl. Acad. Sci. U.S.A. 103 (12): 4711–6. doi:10.1073/pnas.0600113103. PMC 1450236 . PMID 16537405.  ^ http://adisinsight.springer.com/drugs/800034216 ^ Duchossoy Y, David S, Baulieu EE, Robel P (2011). "Treatment of experimental spinal cord injury with 3β-methoxy-pregnenolone". Brain Res. 1403: 57–66. doi:10.1016/j.brainres.2011.05.065. PMID 21704982.  ^ Bianchi M, Baulieu EE (2012). "3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders". Proc. Natl. Acad. Sci. U.S.A. 109 (5): 1713–8. doi:10.1073/pnas.1121485109. PMC 3277154 . PMID 22307636.  ^ Baulieu ÉÉ (2015). "From steroid hormones to depressive states and senile dementias: New mechanistic, therapeutical and predictive approaches". Comptes Rendus Biologies. 338 (8-9): 613–6. doi:10.1016/j.crvi.2015.06.003. PMID 26251072.  ^ Kliewer SA, Lehmann JM, Milburn MV, Willson TM (1999). "The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways". Recent Prog. Horm. Res. 54: 345–67; discussion 367–8. PMID 10548883.  ^ a b Hanukoglu I, Jefcoate CR (1980). " Pregnenolone
Pregnenolone
separation from cholesterol using Sephadex LH-20 mini-columns". Journal of Chromatography A. 190 (1): 256–262. doi:10.1016/S0021-9673(00)85545-4.  ^ Vallée M (2016). "Neurosteroids and potential therapeutics: Focus on pregnenolone". J. Steroid
Steroid
Biochem. Mol. Biol. 160: 78–87. doi:10.1016/j.jsbmb.2015.09.030. PMID 26433186.  ^ a b c Saudan C, Desmarchelier A, Sottas PE, Mangin P, Saugy M (2005). "Urinary marker of oral pregnenolone administration". Steroids. 70 (3): 179–83. doi:10.1016/j.steroids.2004.12.007. PMID 15763596.  ^ a b c Piper T, Schlug C, Mareck U, Schänzer W (2011). "Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration". Drug Test Anal. 3 (5): 283–90. doi:10.1002/dta.281. PMID 21538944.  ^ a b c d e Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I (2013). " Allopregnanolone
Allopregnanolone
elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits". Biol. Psychiatry. 73 (11): 1045–53. doi:10.1016/j.biopsych.2012.12.008. PMC 3648625 . PMID 23348009.  ^ Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, Mattern C, Farr SA (2010). " Brain
Brain
distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration". Eur. J. Pharmacol. 641 (2-3): 128–34. doi:10.1016/j.ejphar.2010.05.033. PMC 3008321 . PMID 20570588.  ^ a b c d e f g J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 665–. ISBN 978-1-4757-2085-3.  ^ a b Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 872–873. ISBN 978-3-88763-075-1. 

CBD Supplement

v t e

Endogenous steroids

Precursors

Cholesterol 22R-Hydroxycholesterol 20α,22R-Dihydroxycholesterol Pregnenolone 11β-Hydroxypregnenolone 17α-Hydroxypregnenolone 21-Hydroxypregnenolone 17α,21-Dihydroxypregnenolone 11β,17α,21-Trihydroxypregnenolone

Corticosteroids

Glucocorticoids

3α,5α-Tetrahydrocorticosterone 5α-Dihydrocorticosterone 11-Deoxycorticosterone 11-Deoxycortisol 11-Ketoprogesterone 21-Deoxycortisol 21-Deoxycortisone Corticosterone Cortisol Cortisone 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone Pregnenolone Progesterone

Mineralocorticoids

5α-Dihydroaldosterone 11-Dehydrocorticosterone
11-Dehydrocorticosterone
(11-oxocorticosterone, 17-deoxycortisone) 11-Deoxycortisol 11-Deoxycorticosterone 11β-Hydroxyprogesterone
11β-Hydroxyprogesterone
(21-deoxycorticosterone) 18-Hydroxy-11-deoxycorticosterone 18-Hydroxycorticosterone 18-Hydroxyprogesterone Aldosterone Corticosterone Cortisol

Sex steroids

Androgens

11-Ketodihydrotestosterone 11-Ketotestosterone 7β-Hydroxyepiandrosterone 11β-Hydroxyandrostenedione Adrenosterone
Adrenosterone
(11-ketoandrostenedione) Androstenediol Androstenedione Androsterone Dehydroandrosterone DHEA DHEA sulfate Dihydrotestosterone Epiandrosterone Epitestosterone 16α-Hydroxyandrostenedione 16α-Hydroxy-DHEA 16α-Hydroxy-DHEA sulfate Testosterone

Metabolites: 3α-Androstanediol 3α-Androstanediol
3α-Androstanediol
glucuronide 3β-Androstanediol 3α,5β-Androstanediol 3β,5β-Androstanediol 5β-Androstanedione 5β-Dihydrotestosterone Androstanetriols Androstenediol
Androstenediol
sulfate Androsterone
Androsterone
glucuronide Androsterone
Androsterone
sulfate Dihydrotestosterone
Dihydrotestosterone
glucuronide Dihydrotestosterone
Dihydrotestosterone
sulfate Etiocholanolone Etiocholanolone
Etiocholanolone
glucuronide Epietiocholanolone Testosterone
Testosterone
glucuronide Testosterone
Testosterone
sulfate

Estrogens

Estranes: Estetrol Estradiol Estrone Estriol 17α-Estradiol 16β- Epiestriol
Epiestriol
(16β-hydroxyestradiol) 17α- Epiestriol
Epiestriol
(16α-hydroxy-17α-estradiol) 16β,17α- Epiestriol
Epiestriol
(16β-hydroxy-17α-estradiol) 2-Hydroxyestradiol 2-Hydroxyestriol 2-Hydroxyestrone 4-Hydroxyestradiol 4-Hydroxyestriol 4-Hydroxyestrone 4-Methoxyestradiol 16α-Hydroxyestrone

Others: 27-Hydroxycholesterol 3α-Androstanediol 3β-Androstanediol 4-Androstenedione 5-Androstenediol DHEA DHEA sulfate 7-Keto-DHEA 7α-Hydroxy-DHEA 16α-Hydroxy-DHEA

Metabolites: 2-Methoxyestradiol 2-Methoxyestrone 4-Methoxyestrone Estradiol
Estradiol
glucuronide Estradiol
Estradiol
sulfate Estrone
Estrone
glucuronide Estrone
Estrone
sulfate Estriol
Estriol
glucuronide Estriol
Estriol
sulfate Lipoidal estradiol
Lipoidal estradiol
(e.g., estradiol stearate, estradiol palmitate)

Progestogens

Progesterone 16α-Hydroxyprogesterone 17α-Hydroxyprogesterone 20α-Dihydroprogesterone 5α-Dihydroprogesterone 11-Deoxycorticosterone 5α-DHDOC

Metabolites: Allopregnanediol Pregnanediol Pregnanediol
Pregnanediol
glucuronide Pregnanetriol

Neurosteroids

Cholestanes: 24S-Hydroxycholesterol Cholesterol

Pregnanes: 3α-Dihydroprogesterone 3β-Dihydroprogesterone 5α-Dihydrocorticosterone 5α-Dihydroprogesterone 5β-Dihydroprogesterone Allopregnanolone Corticosterone DHC DHDOC 11-Deoxycorticosterone Epipregnanolone Isopregnanolone Pregnanolone Pregnenolone Pregnenolone
Pregnenolone
sulfate Progesterone THB THDOC

Androstanes: 3α-Androstanediol 3α-Androstenol 7-Keto-DHEA 7α-Hydroxy-DHEA 7β-Hydroxy-DHEA 7α-Hydroxyepiandrosterone 7β-Hydroxyepiandrosterone Androsterone DHEA DHEA sulfate Etiocholanolone

Pheromones: 3α-Androstenol 3β-Androstenol Androstadienol Androstadienone Androstenone Androsterone Estratetraenol

Others

Vitamin D: 7-Dehydrocholesterol Calcidiol/Calcifediol Calcitriol Cholecalciferol

Others: 7α-Hydroxycholesterol 11α-Hydroxyprogesterone 11β-Hydroxyprogesterone Cholesterol
Cholesterol
sulfate

Biological activity

v t e

Cannabinoid receptor
Cannabinoid receptor
modulators

Receptor (ligands)

CB1

Agonists (abridged; see here for more): 2-AG 2-AGE (noladin ether) 11-Hydroxy-THC α-Amyrin β-Amyrin AB-CHMINACA AM-1172 AM-1220 AM-1221 AM-1235 AM-2201 AM-2232 Anandamide Arvanil AZ-11713908 Cannabinol CB-13 CP 47,497 CP 55,940 Dimethylheptylpyran DEA ECG EGCG Epicatechin Gallocatechol
Gallocatechol
(gallocatechin) Honokiol HU-210 JWH-007 JWH-015 JWH-018 JWH-073 Kavain L-759,633 Levonantradol Menabitan Nabilone Nabitan NADA O-1812 Oleamide Pravadoline Serinolamide A THC (dronabinol) UR-144 WIN 55,212-2 Yangonin

Antagonists: AM-251 AM-6545 Cannabidiol Cannabigerol Drinabant Falcarinol
Falcarinol
(carotatoxin) Hemopressin Ibipinabant LY-320,135 MK-9470 NESS-0327 O-2050 Otenabant PF-514273 PipISB Rimonabant Rosonabant Surinabant Taranabant THCV TM-38837 VCHSR Virodhamine

Antibodies: Brizantin (Бризантин) Dietressa (Диетресса)

Unknown/unsorted: MAFP

CB2

Agonists: 2-AG 2-AGE (noladin ether) 3,3'-Diindolylmethane 4-O-Methylhonokiol α-Amyrin β-Amyrin A-796,260 A-834,735 A-836,339 AM-1172 AM-1221 AM-1235 AM-1241 AM-2232 Anandamide AZ-11713908 Cannabinol Caryophyllene CB-13 CBS-0550 CP-55,940 GW-405,833
GW-405,833
(L-768,242) GW-842,166X HU-308 JTE 7-31 JWH-007 JWH-015 JWH-018 JWH-73 JWH-133 L-759,633 L-759,656 Magnolol MDA-19 Nabitan NADA PF-03550096 S-444,823 SER-601 Serinolamide A UR-144 Tedalinab THC (dronabinol) THCV Tetrahydromagnolol Virodhamine

Antagonists: 4-O-Methylhonokiol AM-630 BML-190 Cannabidiol Honokiol JTE-907 SR-144,528 WIN 54,461 WIN 56,098

NAGly (GPR18)

Agonists: Abnormal cannabidiol ACPA AM251 Anandamide Cannabidiol NADGly THC (dronabinol) O-1602

Antagonists: CID-85469571 O-1918

GPR55

Agonists: 2-AGE (noladin ether) 2-ALPI Abnormal cannabidiol AM-251 CID1011163 CID1252842 CID1792579 CP 55,940 GSK-494581A Lysophosphatidylinositol ML-184 ML-185 ML-186 O-1602 Oleoylethanolamide Palmitoylethanolamide THC (dronabinol)

Antagonists: Cannabidiol CID-16020046 ML-191 ML-192 ML-193 O-1918 PSB-SB-487 PSB-SB-1202 PSB-SB-1203 Tetrahydromagnolol

GPR119

Agonists: 2-Oleoylglycerol Anandamide APD668 AR-231,453 AS-1269574 MBX-2982 N-Oleoyldopamine Oleoylethanolamide Olvanil PSN-375,963 PSN-632,408

Transporter (modulators)

eCBTs

Inhibitors: 5'-DMH-CBD AM-404 AM-1172 Arachidonoyl serotonin Arvanil Cannabidiol Guineensine LY-2183240 O-2093 OMDM-2 Paracetamol
Paracetamol
(acetaminophen) SB-FI-26 UCM-707 URB-597 VDM-11 WOBE490 WOBE491 WOBE492

Enzyme (modulators)

FAAH

Inhibitors: 4-Nonylphenylboronic acid AACOCF3 AM-404 Arachidonoyl serotonin BIA 10-2474 Biochanin A Genistein IDFP JNJ-1661010 JNJ-42165279 JZL-195 Kaempferol LY-2183240 MAFP Palmitoylisopropylamide Paracetamol
Paracetamol
(acetaminophen) PF-3845 PF-04457845 PF-750 SA-47 SA-57 TAK 21d TC-F 2 UCM710 URB-597

Activators: PDP-EA

MAGL

Inhibitors: ABX-1431 IDFP JJKK 048 JW 642 JZL-184 JZL-195 JZP-361 KML 29 MAFP MJN110 NAM Pristimerin URB-602

ABHD6

Inhibitors: JZP-169 JZP-430 KT182 KT185 KT195 KT203 LEI-106 ML294 ML295 ML296 UCM710 WWL-70

ABHD12

Inhibitors: Betulinic acid Maslinic acid MAFP Oleanolic acid Orlistat
Orlistat
(tetrahydrolipstatin) Ursolic acid

Others

Precursors: Phosphatidylethanolamine NAPE Diacylglycerol

Others: 2-PG (directly potentiates activity of 2-AG at CB1 receptor) ARN-272 (FAAH-like anandamide transporter inhibitor)

See also Receptor/signaling modulators Cannabinoids (cannabinoids by structure)

v t e

Glycine receptor
Glycine receptor
modulators

Receptor (ligands)

GlyR

Agonists: β-Alanine β-ABA (BABA) β-AIBA Caesium D-Alanine D-Serine GABA Glycine Hypotaurine Ivermectin L-Alanine L-Proline L-Serine L-Threonine MDL-27531 Milacemide Picolinic acid Propofol Quisqualamine Sarcosine Taurine

Positive modulators: Alcohols (e.g., brometone, chlorobutanol (chloretone), ethanol (alcohol), tert-butanol (2M2P), tribromoethanol, trichloroethanol, trifluoroethanol) Alkylbenzene sulfonate Anandamide Barbiturates (e.g., pentobarbital, sodium thiopental) Chlormethiazole D12-116 Dihydropyridines (e.g., nicardipine) Etomidate Ginseng
Ginseng
constituents (e.g., ginsenosides (e.g., ginsenoside-Rf)) Glutamic acid
Glutamic acid
(glutamate) Ivermectin Ketamine Neuroactive steroids (e.g., alfaxolone, pregnenolone (eltanolone), pregnenolone acetate, minaxolone, ORG-20599) Nitrous oxide Penicillin G Propofol Tamoxifen Tetrahydrocannabinol Triclofos Tropeines (e.g., atropine, bemesetron, cocaine, LY-278584, tropisetron, zatosetron) Volatiles/gases (e.g., chloral hydrate, chloroform, desflurane, diethyl ether (ether), enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, toluene, trichloroethane (methyl chloroform), trichloroethylene) Xenon Zinc

Antagonists: 2-Aminostrychnine 2-Nitrostrychnine 4-Phenyl-4-formyl-N-methylpiperidine αEMBTL Bicuculline Brucine Cacotheline Caffeine Colchicine Colubrine Cyanotriphenylborate Dendrobine Diaboline Endocannabinoids (e.g., 2-AG, anandamide (AEA)) Gaboxadol
Gaboxadol
(THIP) Gelsemine iso-THAZ Isobutyric acid Isonipecotic acid Isostrychnine Laudanosine N-Methylbicuculline N-Methylstrychnine N,N-Dimethylmuscimol Nipecotic acid Pitrazepin Pseudostrychnine Quinolines (e.g., 4-hydroxyquinoline, 4-hydroxyquinoline-3-carboxylic acid, 5,7-CIQA, 7-CIQ, 7-TFQ, 7-TFQA) RU-5135 Sinomenine Strychnine Thiocolchicoside Tutin

Negative modulators: Amiloride Benzodiazepines (e.g., bromazepam, clonazepam, diazepam, flunitrazepam, flurazepam) Corymine Cyanotriphenylborate Daidzein Dihydropyridines (e.g., nicardipine, nifedipine, nitrendipine) Furosemide Genistein Ginkgo constituents (e.g., bilobalide, ginkgolides (e.g., ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M)) Imipramine NBQX Neuroactive steroids (e.g., 3α-androsterone sulfate, 3β-androsterone sulfate, deoxycorticosterone, DHEA sulfate, pregnenolone sulfate, progesterone) Opioids (e.g., codeine, dextromethorphan, dextrorphan, levomethadone, levorphanol, morphine, oripavine, pethidine, thebaine) Picrotoxin
Picrotoxin
(i.e., picrotin and picrotoxinin) PMBA Riluzole Tropeines (e.g., bemesetron, LY-278584, tropisetron, zatosetron) Verapamil Zinc

NMDAR

See here instead.

Transporter (blockers)

GlyT1

ACPPB ALX-1393 ALX-5407 (NFPS) AMG-747 ASP2535 Bitopertin
Bitopertin
(RG1678/RO4917838) CP-802079 Ethanol (alcohol) Glycyldodecylamide GSK1018921 LY-2365109 ORG-24598 ORG-25935
ORG-25935
(SCH-900435) PF-02545920 PF-03463275 PF-04958242 Sarcosine SSR-103,800 SSR-504,734

GlyT2

Amoxapine Ethanol (alcohol) NAGly Opiranserin (VVZ-149) ORG-25543 VVZ-368

See also Receptor/signaling modulators GABA receptor modulators GABAA receptor
GABAA receptor
positive modulators Ionotropic glutamate receptor modulators

v t e

Sigma receptor
Sigma receptor
modulators

σ1

Agonists: 3-PPP 4-PPBP 5-MeO-DMT Alazocine
Alazocine
(SKF-10047) Amantadine ANAVEX2-73 Arketamine BD-737 BD-1052 Captodiame Citalopram CGRP Cloperastine Cocaine Cutamesine
Cutamesine
(SA-4503) Cyclazocine Dehydroepiandrosterone
Dehydroepiandrosterone
(DHEA) (prasterone) Dehydroepiandrosterone
Dehydroepiandrosterone
sulfate (DHEA-S) (prasterone sulfate) Dextrallorphan Dextromethorphan
Dextromethorphan
(DXM) Dextrorphan
Dextrorphan
(DXO) Dimemorfan Dimethyltryptamine
Dimethyltryptamine
(DMT) Ditolylguanidine
Ditolylguanidine
(DTG) Donepezil Eliprodil Escitalopram Fabomotizole
Fabomotizole
(afobazole) Fluoxetine Fluvoxamine Ifenprodil Igmesine
Igmesine
(JO-1784) IPAB Ketamine L-687384 MDMA
MDMA
(midomafetamine) Memantine Methamphetamine Methoxetamine Methylphenidate Nepinalone Neuropeptide Y Noscapine OPC-14523 Opipramol Pentazocine Pentoxyverine
Pentoxyverine
(carbetapentane) PRE-084 Pregnenolone Pregnenolone
Pregnenolone
sulfate Pridopidine Racemethorphan
Racemethorphan
(methorphan) Racemorphan
Racemorphan
(morphanol) UMB-23 UMB-82

Antagonists: 3-PPP AC-927 BD-1008 BD-1031 BD-1047 BD-1060 BD-1063 BD-1067 BMY-14802
BMY-14802
(BMS-181100) CM-156 Dup-734 E-5842 E-52862
E-52862
(S1RA) Haloperidol LR-132 LR-172 MS-377 NE-100 NPC-16377 Panamesine
Panamesine
(EMD-57455) PD-144418 Pentazocine Progesterone Rimcazole
Rimcazole
(BW-234U) Sertraline SR-31742A

Allosteric modulators: Phenytoin; Positive: Methylphenylpiracetam SOMCL-668

Unknown/unsorted: 3-Methoxydextrallorphan 3-MeO-PCP 4C-T-2 4-IBP 4-IPBS 4-MeO-PCP 5-MeO-DALT 5-MeO-DiPT Amitriptyline Azidopamil Chlorpromazine Clemastine Clomipramine Clorgiline D-Deprenyl DiPT DPT Ibogaine Imipramine KCR-12-83.1 Nemonapride Noribogaine RHL-033 RS-67,333 RTI-55 Saffron Safinamide Selegiline Spipethiane Trifluoperazine W-18 YKP10A

σ2

Agonists: 3-PPP Arketamine BD-1047 BD1063 Ditolylguanidine
Ditolylguanidine
(DTG) DKR-1005 DKR-1051 Haloperidol Ifenprodil Ketamine MDMA
MDMA
(midomafetamine) Methamphetamine OPC-14523 Opipramol PB-28 Phencyclidine Siramesine
Siramesine
(Lu 28-179) UKH-1114

Antagonists: AC-927 BD-1008 BD-1067 CM-156 CT-1812 LR-172 MIN-101 Panamesine
Panamesine
(EMD-57455) SAS-0132

Unknown/unsorted: 3-Methoxydextrallorphan 3-MeO-PCE 4-MeO-PCP 5-MeO-DALT 5-MeO-DiPT Clemastine DiPT DPT Ibogaine Nemonapride Nepinalone Noribogaine Pentazocine RS-67,333 Safinamide TMA UMB-23 UMB-82 W-18

Unsorted

Agonists: Berberine Ethylketazocine Fourphit Metaphit Nalbuphine Naluzotan Tapentadol Tenocyclidine

Antagonists: AHD1 AZ66 Lamotrigine Naloxone SM-21 UMB-100 UMB-101 UMB-103 UMB-116 YZ-011 YZ-069 YZ-185

Allosteric modulators: SKF-83959

Unknown/unsorted: 18-Methoxycoronaridine BMY-13980 Butaclamol Caramiphen Carvotroline Chlorphenamine
Chlorphenamine
(chlorpheniramine) Chlorpromazine Cinnarizine Cinuperone Clocapramine Dezocine EMD-59983 Hypericin
Hypericin
(St. John's wort) Fluphenazine Gevotroline
Gevotroline
(WY-47384) Mepyramine
Mepyramine
(pyrilamine) Molindone Perphenazine Pimozide Proadifen Promethazine Propranolol Quinidine Remoxipride SL 82.0715 SR-31747A Tiospirone
Tiospirone
(BMY-13859) Venlafaxine

See also: Receptor/signaling modulators

v t e

Xenobiotic-sensing receptor modulators

CAR

Agonists: 6,7-Dimethylesculetin Amiodarone Artemisinin Benfuracarb Carbamazepine Carvedilol Chlorpromazine Chrysin CITCO Clotrimazole Cyclophosphamide Cypermethrin DHEA (prasterone) Efavirenz Ellagic acid Griseofulvin Methoxychlor Mifepristone Nefazodone Nevirapine Nicardipine Octicizer Permethrin Phenobarbital Phenytoin Pregnanedione (5β-dihydroprogesterone) Reserpine TCPOBOP Telmisartan Tolnaftate Troglitazone Valproic acid

Antagonists: 3,17β-Estradiol 3α-Androstanol 3α-Androstenol 3β-Androstanol 17-Androstanol AITC Ethinylestradiol Meclizine Nigramide J Okadaic acid PK-11195 S-07662 T-0901317

PXR

Agonists: 17α-Hydroxypregnenolone 17α-Hydroxyprogesterone Δ4-Androstenedione Δ5-Androstenediol Δ5-Androstenedione AA-861 Allopregnanediol Allopregnanedione (5α-dihydroprogesterone) Allopregnanolone
Allopregnanolone
(brexanolone) Alpha-Lipoic acid Ambrisentan AMI-193 Amlodipine besylate Antimycotics Artemisinin Aurothioglucose Bile acids Bithionol Bosentan Bumecaine Cafestol Cephaloridine Cephradine Chlorpromazine Ciglitazone Clindamycin Clofenvinfos Chloroxine Clotrimazole Colforsin Corticosterone Cyclophosphamide Cyproterone acetate Demecolcine Dexamethasone DHEA (prasterone) DHEA-S (prasterone sulfate) Dibunate sodium Diclazuril Dicloxacillin Dimercaprol Dinaline Docetaxel Docusate calcium Dodecylbenzenesulfonic acid Dronabinol Droxidopa Eburnamonine Ecopipam Enzacamene Epothilone B Erythromycin Famprofazone Febantel Felodipine Fenbendazole Fentanyl Flucloxacillin Fluorometholone Griseofulvin Guggulsterone Haloprogin Hetacillin potassium Hyperforin Hypericum perforatum
Hypericum perforatum
(St John's wort) Indinavir sulfate Lasalocid sodium Levothyroxine Linolenic acid LOE-908 Loratadine Lovastatin Meclizine Metacycline Methylprednisolone Metyrapone Mevastatin Mifepristone Nafcillin Nicardipine Nicotine Nifedipine Nilvadipine Nisoldipine Norelgestromin Omeprazole Orlistat Oxatomide Paclitaxel Phenobarbital Piperine Plicamycin Prednisolone Pregnanediol Pregnanedione (5β-dihydroprogesterone) Pregnanolone Pregnenolone Pregnenolone
Pregnenolone
16α-carbonitrile Proadifen Progesterone Quingestrone Reserpine Reverse triiodothyronine Rifampicin Rifaximin Rimexolone Riodipine Ritonavir Simvastatin Sirolimus Spironolactone Spiroxatrine SR-12813 Suberoylanilide Sulfisoxazole Suramin Tacrolimus Tenylidone Terconazole Testosterone
Testosterone
isocaproate Tetracycline Thiamylal sodium Thiothixene Thonzonium bromide Tianeptine Troglitazone Troleandomycin Tropanyl 3,5-dimethulbenzoate Zafirlukast Zeranol

Antagonists: Ketoconazole Sesamin

See also Receptor/signaling modulators Nuclear recepto

.