BNN-20 explained

BNN-20, also known as 17β-spiro-(androst-5-en-17,2'-oxiran)-3β-ol, is a synthetic neurosteroid, "microneurotrophin", and analogue of the endogenous neurosteroid dehydroepiandrosterone (DHEA).^{[1] [2]} It acts as a selective, high-affinity, centrally active agonist of the TrkA, TrkB, and p75^NTR, receptors for the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as for DHEA and DHEA sulfate (DHEA-S).^[3] The drug has been suggested as a potential novel treatment for Parkinson's disease and other conditions.

In 2011, the surprising discovery was made that DHEA, as well as DHEA-S, directly bind to and activate the TrkA and p75^NTR with high affinity. DHEA was subsequently also found to bind to the TrkB and TrkC with high affinity, though it notably activated the TrkC but not the TrkB.^[4] DHEA and DHEA-S bound to these receptors with affinities that were in the low nanomolar range (around 5 nM), although the affinities were nonetheless approximately two orders of magnitude lower relative to the highly potent polypeptide neurotrophins (0.01–0.1 nM). In any case, DHEA and DHEA-S were identified as important endogenous neurotrophic factors. These findings may explain the positive association between decreased circulating DHEA levels with age and age-related neurodegenerative diseases.

Subsequently, a series of spiro derivatives of DHEA that had been synthesized and assessed in 2009 as potential neuroprotective agents was re-investigated. Of these, BNN-20 was assayed and found to directly bind to and activate the TrkA, TrkB, and p75^NTR. In addition, it was found to cross the blood–brain barrier and to have strong neuroprotective effects on dopaminergic neurons in vivo in a mouse model of dopaminergic neurodegeneration, which were dependent, at least in part, on activation of the TrkB. Moreover, unlike DHEA, it lacked any hormonal actions. As such, BNN-20 was described as a BDNF mimetic and was proposed as a potential novel treatment for Parkinson's disease and other conditions, particularly of the neurodegenerative variety, like amyotrophic lateral sclerosis.^[5]

See also

• List of neurosteroids
• Anicequol
• BNN-27

Notes and References

1. Calogeropoulou T, Avlonitis N, Minas V, Alexi X, Pantzou A, Charalampopoulos I, Zervou M, Vergou V, Katsanou ES, Lazaridis I, Alexis MN, Gravanis A . Novel dehydroepiandrosterone derivatives with antiapoptotic, neuroprotective activity . J. Med. Chem. . 52 . 21 . 6569–87 . 2009 . 19845386 . 10.1021/jm900468p .
2. Botsakis K, Mourtzi T, Panagiotakopoulou V, Vreka M, Stathopoulos GT, Pediaditakis I, Charalampopoulos I, Gravanis A, Delis F, Antoniou K, Zisimopoulos D, Georgiou CD, Panagopoulos NT, Matsokis N, Angelatou F . BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the "weaver" mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor . Neuropharmacology . 121 . 140–157 . 2017 . 28461162 . 10.1016/j.neuropharm.2017.04.043 . 5071762 .
3. Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A . Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis . PLOS Biol. . 9 . 4 . e1001051 . 2011 . 21541365 . 3082517 . 10.1371/journal.pbio.1001051 . free .
4. Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, Gravanis A . Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors . Endocrinology . 156 . 1 . 16–23 . 2015 . 25330101 . 10.1210/en.2014-1596 . free .
5. Bennett JP, O'Brien LC, Brohawn DG . Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis . Biochem. Pharmacol. . 117 . 68–77 . 2016 . 27498123 . 10.1016/j.bcp.2016.08.001 .