This article is about DHEA sulfate as a hormone. For its use as a medication, see
Prasterone sulfate .
Dehydroepiandrosterone sulfate
Names
IUPAC name
17-Oxoandrost-5-en-3β-yl hydrogen sulfate
Systematic IUPAC name
(3aS ,3bR ,7S ,9aR ,9bS ,11aS )-9a,11a-Dimethyl-1-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H -cyclopenta[a ]phenanthren-7-yl hydrogen sulfate
Other names
Androstenolone sulfate; Prasterone sulfate; Androst-5-en-3β-ol-17-one 3β-sulfate
Identifiers
Abbreviations
DHEA sulfate; DHEA-S; DHEAS
ChemSpider
UNII
InChI=1S/C19H28O5S/c1-18-9-7-13(24-25(21,22)23)11-12(18)3-4-14-15-5-6-17(20)19(15,2)10-8-16(14)18/h3,13-16H,4-11H2,1-2H3,(H,21,22,23)/t13-,14-,15-,16-,18-,19-/m0/s1
N Key: CZWCKYRVOZZJNM-USOAJAOKSA-N
N InChI=1/C19H28O5S/c1-18-9-7-13(24-25(21,22)23)11-12(18)3-4-14-15-5-6-17(20)19(15,2)10-8-16(14)18/h3,13-16H,4-11H2,1-2H3,(H,21,22,23)/t13-,14-,15-,16-,18-,19-/m0/s1
Key: CZWCKYRVOZZJNM-USOAJAOKBK
C[C@]12CC[C@H]3[C@H]([C@@H]1CCC2=O)CC=C4[C@@]3(CC[C@@H](C4)OS(=O)(=O)O)C
Properties
C19 H28 O5 S
Molar mass
368.49 g/mol
Except where otherwise noted, data are given for materials in their
standard state (at 25 °C [77 °F], 100 kPa).
Chemical compound
Dehydroepiandrosterone sulfate , abbreviated as DHEA sulfate or DHEA-S , also known as androstenolone sulfate , is an
endogenous
androstane
steroid that is produced by the
adrenal cortex .
[1] It is the 3β-
sulfate
ester and a
metabolite of
dehydroepiandrosterone (DHEA) and circulates in far greater relative concentrations than DHEA.
[2] The steroid is
hormonally inert and is instead an important
neurosteroid and
neurotrophin .
[2]
Biological activity
Neurosteroid activity
Similarly to other
conjugated steroids, DHEA-S is devoid of
hormonal activity, lacking
affinity for the
steroid hormone receptors .
[3]
[4] However, DHEA-S retains activity as a
neurosteroid and
neurotrophin .
[2] It has been found to act as a
positive allosteric modulator of the
NMDA receptor (50 nM–1 μM),
negative allosteric modulator of the
GABAA and
glycine receptors , and weak
agonist of the
sigma-1 receptor (Kd > 50 μM).
[2]
[5] In addition, DHEA-S has been found to directly bind to and activate the
TrkA and
p75NTR – receptors of neurotrophins like
nerve growth factor (NGF) and
brain-derived neurotrophic factor (BDNF) – with high affinity (around 5 nM).
[2]
[6]
[7]
[8]
Hormonal activity
Although DHEA-S itself is hormonally inert, it has been thought that it can be converted back into DHEA,
[9] which is weakly
androgenic and
estrogenic , and that DHEA in turn can be transformed into more potent androgens like
testosterone and
dihydrotestosterone (DHT) as well as estrogens like
estradiol .
[2]
[1]
[10] As such, it has been thought that DHEA-S is a
prohormone with the potential for androgenic and estrogenic effects.
[2]
[1]
[10] However, a 2005 study found that DHEA could be converted into DHEA-S but found no evidence of conversion of DHEA-S into DHEA.
[11]
Other activity
DHEA-S has also been found to inhibit the
TRPV1 and
TRPC5
transient receptor potential channels and to inhibit the
P2X receptor .
[5]
Biochemistry
Comprehensive overview of
steroidogenesis , showing DHEA, the precursor of DHEA-S, at left among the androgens.
[12]
Biosynthesis
DHEA and DHEA-S are produced in the
zona reticularis of the
adrenal cortex under the control of
adrenocorticotropic hormone (ACTH).
[1] DHEA is synthesized from
cholesterol via the
enzymes
cholesterol side-chain cleavage enzyme (CYP11A1; P450scc) and
17α-hydroxylase/17,20-lyase (CYP17A1), with
pregnenolone and
17α-hydroxypregnenolone as
intermediates .
[13] Then, DHEA-S is formed by
sulfation of DHEA at the C3β position via the
sulfotransferase
enzymes
SULT2A1 and to a lesser extent
SULT1E1 .
[13]
[14]
[15] Whereas DHEA is derived mostly from the adrenal cortex but is also secreted to a lesser extent by the
gonads (10%),
[16] DHEA-S is almost exclusively produced and secreted by the adrenal cortex, with 95 to 100% originating from the adrenal cortex in women.
[1]
[17]
[18] Approximately 10 to 15 mg of DHEA-S is secreted by the adrenal cortex per day in young adults.
[19]
Distribution
Unlike DHEA, which is weakly bound to
albumin , DHEA-S is strongly bound to albumin (i.e., with very high affinity), and this is the reason for its much longer comparative
terminal half-life .
[20]
[21] In contrast to DHEA, DHEA-S is not bound to any extent to
sex hormone-binding globulin (SHBG).
[22]
Whereas DHEA easily crosses the
blood–brain barrier into the
central nervous system ,
[23] DHEA-S poorly crosses the blood–brain barrier.
[24]
Metabolism
DHEA-S can be converted back into DHEA via
steroid sulfatase (STS).
[9] In
premenopausal women, 40 to 75% of circulating testosterone is derived from peripheral
metabolism of DHEA-S, and in
postmenopausal women, over 90% of estrogens, mainly
estrone , are derived from peripheral metabolism of DHEA-S.
[2] A study found that administration of exogenous DHEA-S in women who were pregnant increased circulating levels of estrone and
estradiol .
[25] DHEA-S serves as a
depot for potent androgens like testosterone and dihydrotestosterone in
prostate cancer , which fuel the growth of this cancer.
[26]
The elimination half-life of DHEA-S is 7 to 10 hours, which is far longer than that of DHEA, which has an elimination half-life of only 15 to 30 minutes.
[21]
Elimination
DHEA-S is
excreted in the
urine via the
kidneys .
[27]
Levels
DHEA-S levels throughout life in humans.
[28]
DHEA and DHEA-S are the most abundant circulating steroids in the body.
[29] Plasma levels of DHEA-S are 100 or more times higher than those of DHEA, 5 to 10 times higher than those of
cortisol , 100 to 500 times those of testosterone, and 1,000 to 10,000 times higher than those of estradiol.
[30]
[3]
Levels of DHEA and DHEA-S vary throughout life.
[2]
[1] They remain low during childhood until
adrenarche around 6 to 8 years of age, at which point they markedly increase,
[31] eventually peaking at around 20 to 30 years of age.
[2]
[1] From the third decade of life on, DHEA and DHEA-S levels gradually decrease.
[29] By the age of 70, levels of DHEA and DHEA-S are 80 to 85% lower than those of young adults, and in people more than 80 years of age, DHEA and DHEA-S levels can reach 80 to 90% lower than those of younger individuals.
[29]
DHEA-S levels are higher in men than in women.
[2]
[29]
Reference ranges
Reference ranges for DHEA-S in females
[32]
Tanner stage and average age
Lower limit
Upper limit
Unit
Tanner stage I
>14 days
16
96
μg /dL
Tanner stage II
10.5 years
22
184
Tanner stage III
11.6 years
<15
296
Tanner stage IV
12.3 years
17
343
Tanner stage V
14.5 years
44
332
18–29 years
44
332
30–39 years
31
228
40–49 years
18
244
50–59 years
<15
200
> or =60 years
<15
157
Reference ranges for DHEA-S in males
[32]
Tanner stage and average age
Lower limit
Upper limit
Unit
Tanner stage I
>14 days
<15
120
μg /dL
Tanner stage II
11.5 years
<15
333
Tanner stage III
13.6 years
<15
312
Tanner stage IV
15.1 years
29
412
Tanner stage V
18.0 years
89
457
18–29 years
89
457
30–39 years
65
334
40–49 years
48
244
50–59 years
35
179
> or =60 years
25
131
Medical use
Deficiency
The
Endocrine Society recommends against the therapeutic use of DHEA-S in both healthy women and those with
adrenal insufficiency , as its role is not clear from studies performed so far.
[33] The routine use of DHEA-S and other androgens is discouraged in the treatment of women with low androgen levels due to
hypopituitarism ,
adrenal insufficiency , menopause due to ovarian surgery,
glucocorticoid use, or other conditions associated with low androgen levels; this is because there are limited data supporting improvement in signs and symptoms with therapy and no long-term studies of risk.
[33]
In otherwise elderly women, in whom an age-related fall of DHEA-S may be associated with menopausal symptoms and reduced libido, DHEA-S supplementation cannot currently be said to improve outcomes.
[34]
Childbirth
As the
sodium salt ,
prasterone sodium sulfate , DHEA-S is used as a
pharmaceutical drug in
Japan in the treatment of insufficient
cervical ripening and
cervical dilation during
childbirth .
[35]
[36]
[37]
[38]
[39]
[40]
[41]
Diagnostic use
DHEA-S levels above 1890 μM or 700 to 800 μg/dL are highly suggestive of
adrenal dysfunction because DHEA-S is made by the adrenal glands
[42]
[43] and also synthesized in the brain.
[44] The presence of DHEA-S is therefore used to rule out ovarian or testicular origin of excess androgen.
Women with
hirsutism commonly present with mildly elevated DHEA-S levels.
[45] Common
etiologies for hirsutism include
ovarian dysfunction (
polycystic ovary syndrome ) and
adrenal dysfunction (
congenital adrenal hyperplasia ,
cushing's syndrome ,
androgen secreting tumors); 90% of these cases are caused by
PCOS or are
idiopathic in nature.
[45] However, severely increased DHEA-S levels (>700 μg/dL) necessitate further workup and are almost stem from benign or malignant adrenal alterations.
[45]
Chemistry
DHEA-S, also known as androst-5-en-3β-ol-17-one 3β-sulfate, is a
naturally occurring
androstane
steroid and the C3β
sulfate
ester of DHEA.
References
^
a
b
c
d
e
f
g Risto Erkkola (2006).
The Menopause . Elsevier. pp. 5–.
ISBN
978-0-444-51830-9 .
^
a
b
c
d
e
f
g
h
i
j
k Prough RA, Clark BJ, Klinge CM (2016).
"Novel mechanisms for DHEA action" . J. Mol. Endocrinol . 56 (3): R139–55.
doi :
10.1530/JME-16-0013 .
PMID
26908835 .
^
a
b Walter K.H. Krause (30 November 2008).
Cutaneous Manifestations of Endocrine Diseases . Springer Science & Business Media. pp. 79–.
ISBN
978-3-540-88367-8 . Plasma DHEA-S levels in adult men and women are 100-500 times higher than those of testosterone and 1000-10000 times higher than those of estradiol.
^ Mo Q, Lu SF, Simon NG (2006). "Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity". J. Steroid Biochem. Mol. Biol . 99 (1): 50–8.
doi :
10.1016/j.jsbmb.2005.11.011 .
PMID
16524719 .
S2CID
30489004 .
^
a
b Steven R. King (9 November 2012).
Neurosteroids and the Nervous System . Springer Science & Business Media. pp. 1, 12.
ISBN
978-1-4614-5559-2 .
^ Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A (2011).
"Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis" . PLOS Biol . 9 (4): e1001051.
doi :
10.1371/journal.pbio.1001051 .
PMC
3082517 .
PMID
21541365 .
^ Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, Gravanis A (2015).
"Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors" . Endocrinology . 156 (1): 16–23.
doi :
10.1210/en.2014-1596 .
PMID
25330101 .
^ Gravanis A, Calogeropoulou T, Panoutsakopoulou V, Thermos K, Neophytou C, Charalampopoulos I (2012). "Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells". Sci Signal . 5 (246): pt8.
doi :
10.1126/scisignal.2003387 .
PMID
23074265 .
S2CID
26914550 .
^
a
b Robert Morfin (2 September 2003).
DHEA and the Brain . CRC Press. pp. 28–.
ISBN
978-0-203-30121-0 .
^
a
b Marc A. Fritz; Leon Speroff (28 March 2012).
Clinical Gynecologic Endocrinology and Infertility . Lippincott Williams & Wilkins. pp. 545–.
ISBN
978-1-4511-4847-3 .
^ Hammer F, Subtil S, Lux P, Maser-Gluth C, Stewart PM, Allolio B, Arlt W (2005). "No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies". J. Clin. Endocrinol. Metab . 90 (6): 3600–5.
doi :
10.1210/jc.2004-2386 .
PMID
15755854 .
^ Häggström, Mikael; Richfield, David (2014).
"Diagram of the pathways of human steroidogenesis" . WikiJournal of Medicine . 1 (1).
doi :
10.15347/wjm/2014.005 .
ISSN
2002-4436 .
^
a
b Rainey WE, Nakamura Y (February 2008).
"Regulation of the adrenal androgen biosynthesis" . J. Steroid Biochem. Mol. Biol . 108 (3–5): 281–86.
doi :
10.1016/j.jsbmb.2007.09.015 .
PMC
2699571 .
PMID
17945481 .
^ Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA (2015).
"The Regulation of Steroid Action by Sulfation and Desulfation" . Endocr. Rev . 36 (5): 526–63.
doi :
10.1210/er.2015-1036 .
PMC
4591525 .
PMID
26213785 .
^ Lawrence H Lash (2005).
Drug Metabolism and Transport: Molecular Methods and Mechanisms . Springer Science & Business Media. pp. 353–.
ISBN
978-1-59259-832-8 .
^ Wolf-Bernhard Schill; Frank H. Comhaire; Timothy B. Hargreave (26 August 2006).
Andrology for the Clinician . Springer Science & Business Media. pp. 243–.
ISBN
978-3-540-33713-3 .
^ Gretchen M. Lentz; Rogerio A. Lobo; David M. Gershenson; Vern L. Katz (2012).
Comprehensive Gynecology . Elsevier Health Sciences. pp. 850–.
ISBN
978-0-323-06986-1 .
^ Dimitrios A. Linos; Jon A. van Heerden (5 December 2005).
Adrenal Glands: Diagnostic Aspects and Surgical Therapy . Springer Science & Business Media. pp. 161–.
ISBN
978-3-540-26861-1 .
^ G.A.W. Rook; S. Lightman (6 December 2012).
Steroid Hormones and the T-Cell Cytokine Profile . Springer Science & Business Media. pp. 205–.
ISBN
978-1-4471-0931-0 .
^ Kenneth L. Becker (2001).
Principles and Practice of Endocrinology and Metabolism . Lippincott Williams & Wilkins. pp. 712–.
ISBN
978-0-7817-1750-2 .
^
a
b Bruce Alan White; Susan P. Porterfield (2013).
Endocrine and Reproductive Physiology, Mosby Physiology Monograph Series (with Student Consult Online Access),4: Endocrine and Reproductive Physiology . Elsevier Health Sciences. pp. 164–.
ISBN
978-0-323-08704-9 .
^ Paul M. Coates; M. Coates Paul; Marc Blackman; Marc R. Blackman, Gordon M. Cragg, Mark Levine, Jeffrey D. White, Joel Moss, Mark A. Levine (29 December 2004).
Encyclopedia of Dietary Supplements (Print) . CRC Press. pp. 170–.
ISBN
978-0-8247-5504-1 . {{
cite book }}
: CS1 maint: multiple names: authors list (
link )
^ Joseph E. Pizzorno (2013).
Textbook of Natural Medicine . Elsevier Health Sciences. pp. 711–.
ISBN
978-1-4377-2333-5 .
^ Samuel S. C. Yen; Robert B. Jaffe; Robert L. Barbieri (January 1999).
Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management . Saunders. p.
40 .
ISBN
978-0-7216-6897-0 . Thus, the formation of DHEA-S occurs directly in the brain, particularly because DHEA-S does not cross the blood-brain barrier [...]
^ Nguyen AD, Conley AJ (2008). "Adrenal androgens in humans and nonhuman primates: production, zonation and regulation". Endocr Dev . Endocrine Development. 13 : 33–54.
doi :
10.1159/000134765 .
ISBN
978-3-8055-8580-4 .
PMID
18493132 .
^ Penning TM (2018).
"Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer" . Vitam. Horm . Vitamins and Hormones. 108 : 309–331.
doi :
10.1016/bs.vh.2018.01.007 .
ISBN
9780128143612 .
PMC
6226251 .
PMID
30029732 .
^ S.S. Nussey; S.A. Whitehead (8 April 2013).
Endocrinology: An Integrated Approach . CRC Press. pp. 158–.
ISBN
978-0-203-45043-7 .
^ Mark A. Sperling (10 April 2014).
Pediatric Endocrinology E-Book . Elsevier Health Sciences. pp. 485–.
ISBN
978-1-4557-5973-6 .
^
a
b
c
d Philip E. Harris; Pierre-Marc G. Bouloux (24 March 2014).
Endocrinology in Clinical Practice, Second Edition . CRC Press. pp. 521–.
ISBN
978-1-84184-952-2 .
^ Abraham Weizman (1 February 2008).
Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment . Springer Science & Business Media. pp. 261–.
ISBN
978-1-4020-6854-6 .
^ Douglas T. Carrell; C. Matthew Peterson (23 March 2010).
Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice . Springer Science & Business Media. pp. 158–.
ISBN
978-1-4419-1436-1 .
^
a
b
Dehydroepiandrosterone Sulfate (DHEA-S), Serum
Archived 2018-03-14 at the
Wayback Machine at Mayo Foundation For Medical Education And Research. Retrieved July 2012
^
a
b Wierman, Margaret E.; Arlt, Wiebke; Basson, Rosemary; Davis, Susan R.; Miller, Karen K.; Murad, Mohammad H.; Rosner, William; Santoro, Nanette (2014).
"Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline" . The Journal of Clinical Endocrinology & Metabolism . 99 (10): 3489–510.
doi :
10.1210/jc.2014-2260 .
PMID
25279570 .
^ Elraiyah, Tarig; Sonbol, Mohamad Bassam; Wang, Zhen; Khairalseed, Tagwa; Asi, Noor; Undavalli, Chaitanya; Nabhan, Mohammad; Altayar, Osama; Prokop, Larry; Montori, Victor M.; Murad, Mohammad Hassan (2014).
"The Benefits and Harms of Systemic Dehydroepiandrosterone (DHEA) in Postmenopausal Women With Normal Adrenal Function: A Systematic Review and Meta-analysis" . The Journal of Clinical Endocrinology & Metabolism . 99 (10): 3536–42.
doi :
10.1210/jc.2014-2261 .
PMC
5393492 .
PMID
25279571 .
^ J. Elks (14 November 2014).
The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies . Springer. pp. 641–.
ISBN
978-1-4757-2085-3 .
^ John W. Blunt; Murray H. G. Munro (19 September 2007).
Dictionary of Marine Natural Products with CD-ROM . CRC Press. pp. 1075–.
ISBN
978-0-8493-8217-8 .
^ A. Kleemann; J. Engel; B. Kutscher; D. Reichert (14 May 2014).
Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs . Thieme. pp. 2441–2442.
ISBN
978-3-13-179525-0 .
^ Martin Negwer; Hans-Georg Scharnow (2001).
Organic-chemical drugs and their synonyms: (an international survey) . Wiley-VCH. p. 1831.
ISBN
978-3-527-30247-5 . 3β-Hydroxyandrost-5-en-17-one hydrogen sulfate = (3β)-3-(Sulfooxy)androst-5-en-17-one. R: Sodium salt (1099-87-2). S: Astenile, Dehydroepiandrosterone sulfate sodium, DHA-S, DHEAS, KYH 3102, Mylis, PB 005, Prasterone sodium sulfate, Teloin
^ Jianqiu Y (1992). "Clinical Application of Prasterone Sodium Sulfate". Chinese Journal of New Drugs . 5 : 015.
^ Sakaguchi M, Sakai T, Adachi Y, Kawashima T, Awata N (1992).
"The biological fate of sodium prasterone sulfate after vaginal administration. I. Absorption and excretion in rats" . J. Pharmacobio-Dyn . 15 (2): 67–73.
doi :
10.1248/bpb1978.15.67 .
PMID
1403604 .
^ Sakai, Takanori; Sakaguchi, Minoru; Adachi, Yoshiko; Kawashima, Tsuneo; Awata, Norio (1992). "The Biological Fate of Sodium Prasterone Sulfate after Vaginal Administration II: Distribution after Single and Multiple Administration to Pregnant Rats". 薬物動態 . 7 (1): 87–101.
doi :
10.2133/dmpk.7.87 .
^ Somani N, Harrison S, Bergfeld WF (2008). "The clinical evaluation of hirsutism". Dermatologic Therapy . 21 (5): 376–91.
doi :
10.1111/j.1529-8019.2008.00219.x .
PMID
18844715 .
S2CID
34029116 .
^
"Polycystic Ovarian Syndrome Workup" .
eMedicine . 25 October 2011. Retrieved 19 November 2011 .
^ Vaudry, H.; Do Rego, J. L.; Burel, D.; Luu-The, V.; Pelletier, G.; Vaudry, D.; Tsutsui, K. (2011).
"Neurosteroid Biosynthesis in the Brain of Amphibians" . Frontiers in Endocrinology . 2 : 79.
doi :
10.3389/fendo.2011.00079 .
PMC
3355965 .
PMID
22649387 .
^
a
b
c Sachdeva, Silonie (2010).
"Hirsutism: Evaluation and Treatment" . Indian Journal of Dermatology . 55. 1 (1): 3–7.
doi :
10.4103/0019-5154.60342 .
PMC
2856356 .
PMID
20418968 .
Ionotropic
GABAA Tooltip γ-Aminobutyric acid A receptor
Positive modulators (abridged; see
here for a full list):
α-EMTBL
Alcohols (e.g.,
drinking alcohol ,
2M2B )
Anabolic steroids
Avermectins (e.g.,
ivermectin )
Barbiturates (e.g.,
phenobarbital )
Benzodiazepines (e.g.,
diazepam )
Bromide compounds (e.g.,
potassium bromide )
Carbamates (e.g.,
meprobamate )
Carbamazepine
Chloralose
Chlormezanone
Clomethiazole
Dihydroergolines (e.g.,
ergoloid (dihydroergotoxine) )
Etazepine
Etifoxine
Fenamates (e.g.,
mefenamic acid )
Flavonoids (e.g.,
apigenin ,
hispidulin )
Fluoxetine
Flupirtine
Imidazoles (e.g.,
etomidate )
Kava constituents (e.g.,
kavain )
Lanthanum
Loreclezole
Monastrol
Neuroactive steroids (e.g.,
allopregnanolone ,
cholesterol ,
THDOC )
Niacin
Niacinamide
Nonbenzodiazepines (e.g.,
β-carbolines (e.g.,
abecarnil ),
cyclopyrrolones (e.g.,
zopiclone ),
imidazopyridines (e.g.,
zolpidem ),
pyrazolopyrimidines (e.g.,
zaleplon ))
Norfluoxetine
Petrichloral
Phenols (e.g.,
propofol )
Phenytoin
Piperidinediones (e.g.,
glutethimide )
Propanidid
Pyrazolopyridines (e.g.,
etazolate )
Quinazolinones (e.g.,
methaqualone )
Retigabine (ezogabine)
ROD-188
Skullcap constituents (e.g.,
baicalin )
Stiripentol
Sulfonylalkanes (e.g.,
sulfonmethane (sulfonal) )
Topiramate
Valerian constituents (e.g.,
valerenic acid )
Volatiles /
gases (e.g.,
chloral hydrate ,
chloroform ,
diethyl ether ,
paraldehyde ,
sevoflurane )
Negative modulators:
1,3M1B
3M2B
11-Ketoprogesterone
17-Phenylandrostenol
α3IA
α5IA (LS-193,268)
β-CCB
β-CCE
β-CCM
β-CCP
β-EMGBL
Anabolic steroids
Amiloride
Anisatin
β-Lactams (e.g.,
penicillins ,
cephalosporins ,
carbapenems )
Basmisanil
Bemegride
Bicyclic phosphates (
TBPS ,
TBPO ,
IPTBO )
BIDN
Bilobalide
Bupropion
CHEB
Chlorophenylsilatrane
Cicutoxin
Cloflubicyne
Cyclothiazide
DHEA
DHEA-S
Dieldrin
(+)-DMBB
DMCM
DMPC
EBOB
Etbicyphat
FG-7142 (ZK-31906)
Fiproles (e.g.,
fipronil )
Flavonoids (e.g.,
amentoflavone ,
oroxylin A )
Flumazenil
Fluoroquinolones (e.g.,
ciprofloxacin )
Flurothyl
Furosemide
Golexanolone
Iomazenil (123 I)
IPTBO
Isopregnanolone (sepranolone)
L-655,708
Laudanosine
Lindane
MaxiPost
Morphine
Morphine-3-glucuronide
MRK-016
Naloxone
Naltrexone
Nicardipine
Nonsteroidal antiandrogens (e.g.,
apalutamide ,
bicalutamide ,
enzalutamide ,
flutamide ,
nilutamide )
Oenanthotoxin
Pentylenetetrazol (pentetrazol)
Phenylsilatrane
Picrotoxin (i.e.,
picrotin ,
picrotoxinin and
dihydropicrotoxinin )
Pregnenolone sulfate
Propybicyphat
PWZ-029
Radequinil
Ro 15-4513
Ro 19-4603
RO4882224
RO4938581
Sarmazenil
SCS
Suritozole
TB-21007
TBOB
TBPS
TCS-1105
Terbequinil
TETS
Thujone
U-93631
Zinc
ZK-93426
GABAA -ρ Tooltip γ-Aminobutyric acid A-rho receptor
Metabotropic
GABAB Tooltip γ-Aminobutyric acid B receptor
GR Tooltip Glucocorticoid receptor
Receptor (
ligands )
GlyR Tooltip Glycine receptor
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 constituents (e.g.,
ginsenosides (e.g.,
ginsenoside-Rf ))
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 (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 (i.e.,
picrotin and
picrotoxinin )
PMBA
Riluzole
Tropeines (e.g.,
bemesetron ,
LY-278584 ,
tropisetron ,
zatosetron )
Verapamil
Zinc
NMDAR Tooltip N-Methyl-D-aspartate receptor
Transporter (
blockers )
GlyT1 Tooltip Glycine transporter 1
GlyT2 Tooltip Glycine transporter 2
Angiopoietin
CNTF
EGF (ErbB)
FGF
FGFR1
FGFR2
Agonists:
Ersofermin
FGF (
1 ,
2 (bFGF) ,
3 ,
4 ,
5 ,
6 ,
7 (
KGF ),
8 ,
9 ,
10 (KGF2) ,
17 ,
18 ,
22 )
Palifermin
Repifermin
Selpercatinib
Sprifermin
Trafermin
FGFR3
FGFR4 Unsorted
HGF (c-Met)
IGF
LNGF (p75NTR )
PDGF
RET (GFL)
SCF (c-Kit)
TGFβ
Trk
TrkA
Negative allosteric modulators:
VM-902A
TrkB
Agonists:
3,7-DHF
3,7,8,2'-THF
4'-DMA-7,8-DHF
7,3'-DHF
7,8-DHF
7,8,2'-THF
7,8,3'-THF
Amitriptyline
BDNF
BNN-20
Deoxygedunin
Deprenyl
Diosmetin
DMAQ-B1
HIOC
LM22A-4
N-Acetylserotonin
NT-3
NT-4
Norwogonin (5,7,8-THF)
R7
R13
TDP6
TrkC
VEGF Others
Additional growth factors:
Adrenomedullin
Colony-stimulating factors (see
here instead)
Connective tissue growth factor (CTGF)
Ephrins (
A1 ,
A2 ,
A3 ,
A4 ,
A5 ,
B1 ,
B2 ,
B3 )
Erythropoietin (see
here instead)
Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
Glia maturation factor (GMF)
Hepatoma-derived growth factor (HDGF)
Interleukins /
T-cell growth factors (see
here instead)
Leukemia inhibitory factor (LIF)
Macrophage-stimulating protein (MSP; HLP, HGFLP)
Midkine (NEGF2)
Migration-stimulating factor (MSF; PRG4)
Oncomodulin
Pituitary adenylate cyclase-activating peptide (PACAP)
Pleiotrophin
Renalase
Thrombopoietin (see
here instead)
Wnt signaling proteins
Additional growth factor receptor modulators:
Cerebrolysin (neurotrophin mixture)
AMPAR Tooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KAR Tooltip Kainate receptor
NMDAR Tooltip N-Methyl-D-aspartate receptor
TRPA
Activators
4-Hydroxynonenal
4-Oxo-2-nonenal
4,5-EET
12S-HpETE
15-Deoxy-Δ12,14 -prostaglandin J2
α-Sanshool (
ginger ,
Sichuan and
melegueta peppers )
Acrolein
Allicin (
garlic )
Allyl isothiocyanate (
mustard ,
radish ,
horseradish ,
wasabi )
AM404
ASP-7663
Bradykinin
Cannabichromene (
cannabis )
Cannabidiol (
cannabis )
Cannabigerol (
cannabis )
Cinnamaldehyde (
cinnamon )
CR gas (dibenzoxazepine; DBO)
CS gas (2-chlorobenzal malononitrile)
Cuminaldehyde (
cumin )
Curcumin (
turmeric )
Dehydroligustilide (
celery )
Diallyl disulfide
Dicentrine (
Lindera spp.)
Farnesyl thiosalicylic acid
Formalin
Gingerols (
ginger )
Hepoxilin A3
Hepoxilin B3
Hydrogen peroxide
Icilin
Isothiocyanate
JT-010
Ligustilide (
celery ,
Angelica acutiloba )
Linalool (
Sichuan pepper ,
thyme )
Methylglyoxal
Methyl salicylate (
wintergreen )
N-Methylmaleimide
Nicotine (
tobacco )
Oleocanthal (
olive oil )
Paclitaxel (
Pacific yew )
Paracetamol (acetaminophen)
PF-4840154
Phenacyl chloride
Polygodial (
Dorrigo pepper )
Shogaols (
ginger ,
Sichuan and
melegueta peppers )
Tear gases
Tetrahydrocannabinol (
cannabis )
Tetrahydrocannabiorcol
Thiopropanal S-oxide (
onion )
Umbellulone (Umbellularia californica )
WIN 55,212-2
Blockers
TRPC
TRPM
TRPML
TRPP
TRPV
Activators
2-APB
5',6'-EET
9-HODE
9-oxoODE
12S-HETE
12S-HpETE
13-HODE
13-oxoODE
20-HETE
α-Sanshool (
ginger ,
Sichuan and
melegueta peppers )
Allicin (
garlic )
AM404
Anandamide
Bisandrographolide (
Andrographis paniculata )
Camphor (
camphor laurel ,
rosemary ,
camphorweed ,
African blue basil ,
camphor basil )
Cannabidiol (
cannabis )
Cannabidivarin (
cannabis )
Capsaicin (
chili pepper )
Carvacrol (
oregano ,
thyme ,
pepperwort ,
wild bergamot , others)
DHEA
Diacyl glycerol
Dihydrocapsaicin (
chili pepper )
Estradiol
Eugenol (
basil ,
clove )
Evodiamine (
Euodia ruticarpa )
Gingerols (
ginger )
GSK1016790A
Heat
Hepoxilin A3
Hepoxilin B3
Homocapsaicin (
chili pepper )
Homodihydrocapsaicin (
chili pepper )
Incensole (
incense )
Lysophosphatidic acid
Low
pH (acidic conditions)
Menthol (
mint )
N-Arachidonoyl dopamine
N-Oleoyldopamine
N-Oleoylethanolamide
Nonivamide (PAVA) (
PAVA spray )
Nordihydrocapsaicin (
chili pepper )
Paclitaxel (
Pacific yew )
Paracetamol (acetaminophen)
Phenylacetylrinvanil
Phorbol esters (e.g.,
4α-PDD )
Piperine (
black pepper ,
long pepper )
Polygodial (
Dorrigo pepper )
Probenecid
Protons
RhTx
Rutamarin (
Ruta graveolens )
Resiniferatoxin (RTX) (
Euphorbia resinifera /
pooissonii )
Shogaols (
ginger ,
Sichuan and
melegueta peppers )
Tetrahydrocannabivarin (
cannabis )
Thymol (
thyme ,
oregano )
Tinyatoxin (
Euphorbia resinifera /
pooissonii )
Tramadol
Vanillin (
vanilla )
Zucapsaicin
Blockers
CAR Tooltip Constitutive androstane receptor
PXR Tooltip Pregnane X receptor