I've been kicking this idea around for awhile since doing some research on Faerun lore for Path of Evil.
According to the Faerun wiki, one of the demon/devil lords plots involves bringing Abeir-Toril into the Hells. Sounds like the beginnings of a solid plot right, to stop them from doing so? Well yeah, if you want something easy to accomplish.
No, instead our plot starts after Abier-Toril has already been brought into the Hells. With chaos everywhere, the Lords of Waterdeep have sent out a call to anyone willing to aid them. Their goal is to collect various artifacts (or activate them or whatever) that will be used to bring Toril back into the Prime. The Lords have a portal the players can use to get where they need to go to collect/activate etc. Even evil aligned players would have an incentive to do this, since being in the Hells probably interferes with their own evil plans.
So what you'd have is a central base with portals anywhere a designer would want to go, and carte blanche to do whatever to the location thanks to the shift to the Hells. Obviously this would be a high/epic level adventure.