|Systematic (IUPAC) name|
|Mol. mass||316.483 g/mol|
|(what is this?)|
Pregnenolone (3β-hydroxypregn-5-en-20-one), also known as P5, is an endogenous steroid hormone. It is the precursor of the progestogens, mineralocorticoids, glucocorticoids, androgens, and estrogens, as well as the neuroactive steroids. In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.
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 many steroid hormones, it is hydrophobic. Its esterified version, pregnenolone sulfate, is water-soluble.
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 anterior pituitary tropic hormones, such as ACTH, FSH, LH.
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.
Pregnenolone and its sulfate, like DHEA and its 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 and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning. Pregnenolone is also being considered as a potential treatment for schizophrenia.
Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulator of the GABAA receptor as well as a positive allosteric modulator of the NMDA receptor. In addition, it 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.
Pregnenolone, a molecule produced by the brain, acts as a natural defense mechanism against effects of cannabis/marijuana in animals. Pregnenolone prevents THC/Tetrahydrocannabinol, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC/Tetrahydrocannabinol causes the intoxicating effects of cannabis/marijuana.
Presumably, there must be a reason why 16 position is selectively hydrogenated.
A Chinese patent was recently published also discussing the synthesis of this steroid.
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- Dan Lednicer: Steroid Chemistry at a Glance, page 86.
- CN 103265600
- Goswami, A.; Kotoky, R.; Rastogi, R. C.; Ghosh, A. C. (2003). "A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate". Organic Process Research & Development 7 (3): 306. doi:10.1021/op0200625.