Immediate incapacitation.

If that is the goal, I don't know the answer, at least I'm not sure.

Some years ago I corresponded with Paul Matthews a bit. Very nice fellow and I have a couple of his books. He favored the .375 as you say and the .45-70, two cartridges I like also.

I used the .375 for years and shot quite a few deer with it. Truth is though, I agree more with Finn Aagaard who said he didn't notice the .375 made any quicker kills than many smaller cartridges on smaller plains game.

Deer I shot with the .375 ran when hit in the lungs and dropped at the shot when hit in the spine, just like the results when hit with many other cartridges I've used on them.

I mostly used 300 grain Hornadys and had no complaints, but a lighter bullet like you suggest might have actually been a quicker killer.

The .45-70 is intriguing, as maybe it was just me, but I found it to be a very fast stopper with my Lee 402 grain hollow Point cast bullet. I didn't shoot a lot of deer with that load, and I did shoot a bear and a couple range cattle, too. It was extremely effective at the short ranges I used it at.

I've shot whitetails with the 6.5x55, .300 Savage, .30-06, 7x57, .348 Winchester, .45-70, .375 H&H, 7.62x39, 9.3x57, and maybe one or two more. I can't say I saw a noticeable killing "SPEED" difference in any of them. Never shot a deer with a shotgun.

Tatume, my brother swears by the .45-70 with 300 grain HP's, and that is a "fast" combination to be sure, so I imagine your .45/300/2500 must be an absolute bomb on them!