Pregnenolone

From DrugPedia: A Wikipedia for Drug discovery

Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone is a GABA_B antagonist and increases neurogenesis in the hippocampus.<ref name=Mayo2005>Mayo, W; Lemaire, V; Malaterre, J; Rodriguez, Jj; Cayre, M; Stewart, Mg; Kharouby, M; Rougon, G; Le, Moal, M; Piazza, Pv; Abrous, Dn (Jan 2005). "Pregnenolone Sulfate Enhances Neurogenesis and Psa-Ncam in Young and Aged Hippocampus". Neurobiology of Aging 26 (1): 103–14. doi:10.1016/j.neurobiolaging.2004.03.013. PMID 15585350. </ref>

Pubchem(8955)

A 21-carbon steroid, derived from CHOLESTEROL and found in steroid hormone-producing tissues. Pregnenolone is the precursor to GONADAL STEROID HORMONES and the adrenal CORTICOSTEROIDS.

Drug Type: Small Molecule; Experimental

KEGG Pathway(C01953,D00143)

C21-Steroid hormone metabolism

**Physiochemical properties of Estriol:**
Physical Property	Value	Units	Temp (deg C)	Source
Melting Point	192	deg C		EXP
log P (octanol-water)	4.22	(none)		EXP
Water Solubility	7.06	mg/L	37	EXP
Vapor Pressure	1.03E-08	mm Hg	25	EST
Henry's Law Constant	1.17E-08	atm-m3/mole	25	EST
Atmospheric OH Rate Constant	1.20E-10	cm3/molecule-sec	25	EST

**Toxicity:**
Organism	Test Type	Route	Reported Dose (Normalized Dose)	Effect	Source
mouse	LD	intraperitoneal	> 200mg/kg (200mg/kg)		Journal of Medicinal Chemistry. Vol. 11, Pg. 117, 1968.

[edit] Chemistry

Like other steroids, pregnenolone consists of four interconnected cyclic hydrocarbons. It contains ketone and hydroxyl functional groups, two methyl branches, and a double bond at C5, in the B cyclic hydrocarbon ring. Like all steroid hormones, it is hydrophobic. Its esterified version, pregnenolone sulfate, is water-soluble.

[edit] Synthesis

Image:DHEA1.svg

Production of Pregnenolone from Cholesteol and further metabolism

Image:Reaction-Pregnenolone-Progesterone2.png

Reaction: Pregnenolone-Progesterone

Pregnenolone is synthesized from cholesterol. This conversion involves hydroxylation at the side-chain at 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 pituitary tropic hormones, such as ACTH, FSH, LH.

[edit] Prohormone

Pregnenolone undergoes further steroid metabolism in one of three ways.

Pregnenolone can be converted to progesterone. The critical enzyme step is two-fold using a 3-beta-hydroxysteroid dehydrogenase and a delta 4-5 isomerase. The latter transfers the double bond from C5 to C4 on the A ring. Progesterone is the entry into the delta-4-pathway, resulting in production of 17-hydroxy progesterone and androstenedione, precursor to testosterone and estrone. Aldosterone and corticosteroids are also derived from progesterone or its derivatives.

Pregnenolone can be converted to 17-hydroxy-pregnenolone by the enzyme 17α-hydroxylase (CYP17A1). Using this pathway, termed delta-5 pathway, the next step is conversion to dehydroepiandrosterone (DHEA) using a desmolase. DHEA is the precursor of androstenedione.

Pregnenolone can be converted to androsta-5,16-dien-3 beta-ol by 16-ene synthetase.

[edit] Neurosteroid

Pregnenolone and its sulfate, like dehydroepiandrosterone and its sulfate and progesterone, belong to the group of neurosteroids that are found in high concentrations in certain areas in the brain, and are synthesized there. Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning.<ref>Vallée M, Mayo W, Le Moal M (2001). "Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging.". Brain Res Brain Res Rev 37 (1-3): 301–12. doi:10.1016/S0165-0173(01)00135-7. PMID 11744095. </ref>