I think that it it is possible to produce a snappy answer -but often their isn't a SINGLE reason for a particular action. I learnt of the hydrogen-bond between the 4-OH and the amine in the mid-90s, but that was before science REALLY looked at hydrogen-bonding as explanation for the CNS activity of many compounds.
I was quite surprised that this idea is 'new' but I hope people can extend it to include many, many compounds.
I mean, I'm pleased that Izo brought it up but you would be amazed by how little it's action is considered. It doesn't work with the majority of actives but I would argue that people with an eye to design should consider it.
It's just one more of those numerous functions that make a compound cross the BBB.
To be fair, RO5 is a much better and more general key and yet things like Δ9-THC ARE active. I do not know the details, but protein binding are key. I should add that I heartily disagree with people designing RCs that rely on protein binding. There isn't the technology to check safety.
Can you imagine being one of the chemists who developed thalidomide, TAB08 or even (and this is the worst) rosiglitazone. The first was banned immediately, the latter ONLY destroyed the lives of trial subjects (All Trials would have exposed risk) but the latter is still used and kills about 810,000 people annum (compared to people given alternative). Which is worse, which shows the most cowardice?
You cannot claim that the evidence is unavailable.... but rosiglitazon had a HUGE amount of money invested. That is what is scary. The experts can see a problem but their NDas mean they cannot speak out. Oh, and for those who say that they SHOULD speak out, you would be amazed at the legal and illegal pressure applies.