I'm an engineer by trade, but spend quite a bit of time in pharmacology and molecular biology research in my free time.

One of the proposal papers caught my eye:

https://lacuna.tiptreesystems.com/hypothesis/why-receptor-hu...

  > " ... a ligand that binds tightly and stays bound a long time should produce a strong intracellular signal, a weak binder a faint one."

When a ligand binds to the ligand binding pocket, the contact points it makes with the proteins inside (called "cofactors") and the strength of each contact point (measured in van der Waals force) modulate the distinct transcriptional effect.

This is called "conformation": the shape it takes in the ligand binding pocket.

So it is not necessarily residence time and overall binding affinity that modulate transcriptional effect.

A very good example of this is the androgen Trestolone/MENT, which is an order of magnitude more potent than Testosterone but displays similar relative binding affinity for the androgen receptor:

https://en.wikipedia.org/wiki/Trestolone

This potency is due to the specific conformational shape it takes within the AR binding pocket.