- 10-25-2003, 10:06 AM
Here is a tentative structure for THG. I am not 100% sure as the name tetrahydrogestrinone is not very specific. This is my best guess at the moment based on the structure of gestrinone. Gestrinone has relative binding affinities(RBA) for the progesterone receptor (PR) and androgen receptor (AR) of 76 and 83 versus progesterone and testosterone respectively. This means that gestrinone has roughly equal affinity for the PR and AR (a ratio of 1). Trenbolone, on the other hand has RBA's of 74 and 197 for the PR and AR respectively (a ratio of 2.67 AR:PR). I would guess that THG would have a profile similar to that of gestrinone (a ratio closer to 1) with possibly a little more AR affinity. This depends on the molecule being enzymatically converted to a 3-one in the body. If not, then you are left with a relatively less active diol.
- 10-25-2003, 10:07 AM
10-25-2003, 08:17 PM
Maybe the 3-hydroxy has less impact on the receptor binding than typical molecules. Notice the structure for stanozolol...it completely eliminates the necessity for either a 3-one or 3-ol which most associate with potency (read: receptor affinity). The important factor to consider is the electron density of the molecule and conformational stress it applies to the poly-ring. Does the increased electron density for stanozolol equate to the receptor affinity of a 3-one? Apparently so or it would not be active. This leads to the general observation that receptor affinity is GREATLY increased with 4,9,11-trienes such as in the case of methyl trenbolone. Both of the compounds you attached should share similiar conformations to methyl tren due to their double bond placements.
I'll bet you're closer to identifying the mystery compound than anyone else...great post!
BTW, I think your AR values above are off by a factor of 10.
10-25-2003, 09:40 PM
The important factor for the substituent group at C-3 is primarily to act as a hydrogen bond acceptor for the glutamine at position 711 and the arginine at position 752 at the end of helix 5 in the ligand binding domain of the androgen receptor. A ketone group does this very effectively (which is why almost all of the major endogenous steroids have a 3-ketone group: cortisol, progesterone, aldosterone, testosterone, DHT with estradiol, estriol and estrone as the exceptions). Stanozolol does not have a 3-ketone group, but does have a nitrogen that can act as a hydrogen bond acceptor in the additional ring adjacent to the a-ring. Danazol is similar to stanozolol in that it has an extra ring, but contains an oxygen in the ring off of the C-3 position that can act as a hydrogen bond acceptor. While the added rigidity of the di and trienes does allow for more exact docking of the molecule in the ligand binding domain, it must still fulfill the necessary hydrogen bonding etc... in order to cause a conformational change in the receptor which results in receptor activation. Size, shape and charge. While a rigid diol may have the size and shape necessary to dock with the LBD, it will still lack the charge requirement at the A-ring necessary for tight binding of the molecule to the receptor, a slow off rate and ultimately receptor activation and stabilization. Maybe I am wrong, but I have yet to see a diol with strong relative binding affinity without being converted to a 3-ketone.
Also, could you let me know why you think my RBA's are off by a factor of 10?
10-25-2003, 11:27 PM
You are very thorough and technically correct in your response. As you have a thorough understandng of receptor activity you will no doubt recognize that what I have posted is also technically correct but dumbed down just a bit for the average-advanced member.
Regardless of which specie is providing the density the basic requirements will be a partially positive hydrogen attracting an electron pair (at its most basic level). As you point out it can be a keto group, nitrogen, or oxygen atom that can act as the donor.
What we have is a basic question of which is more influential in determining receptor affinity: bonding potential at C-3 or conformational structure? IMO, the electron delocalization (hence stability and also structural integrity) afforded by the extended conjugation of the 4,9,11 or even just the 9,11-ene's are more influential for receptor affinities. It is true that a typical 3-keto has enough bonding potential to affect conformational distrortions of the entire ring structure when C-17 is viewed as a weak attachment point for planar alignment. In a nutshell, if the need to strongly attach at C-3 is bypassed via diene or triene induced structural rigidity then the importance of that hydrogen bond is decreased or perhaps even eliminated. This argument applies to 4,9,11 triene's or 9,11 diene's in general.
With respect to the molecule that you presented, the notable absence of the 4,5-double bond will allow the alpha ring to assume a full chair conformation. Thus, even as a 3-ol the molecule should present a high affinity due to steric location and decreased proximity. In theory, the lack of alpha ring unsaturation should allow affinities that are in magnitude with 3-alpha's.
...which leads me to my reply to your diol comment: a 3a,17b-diol is VERY active compound (more so androgenic than anabolic but both values are increased dramatically). This is basis for a simple observation that even 3-ol's can bind to receptors strongly if given the proper steriochemistry...such as with an unsaturated alpha ring substituted 3b-ol.
As for why I believe your values are off: all my references indicate RBA's for a general 4,9,11 triene in the magnitude of 500 each (V.P., S.V., and L.A.). This is regardless of substituents at C-17...acetates up to undec's. I have not referenced the base molecule values so I could be wrong but the trend of increased activity with conformational rigidity cannot be denied.
10-27-2003, 05:56 PM
agree to disagree
I think we will have to agree to disagree as I have yet to see a diol that has any substantial binding affinity. I would love to see some binding data on triene diol. Would clear some things up
As for the binding data, these are published RBA's using tritiated promegestone and methyltrienolone as the labelling agents for PR and AR rtespectively with testosterone arbitrarily set at 100% of binding at the AR and progesterone at 100% of binding for the PR.
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