I've been running a 250 in '37 truck for 25 years now, it has a T350 automatic with a 3.08 rear axle and 28" tall tires. It has plenty of power for the 3300lb truck, will run down the highway at 75 - 80 mph all day long. The faster you drive, the less fuel mileage you get, mostly due to the aerodynamics of the truck. At 65mph,it will get 21 mpg with dual Carter W-1 carburetors and the A/C running cold.
The 250 doesn't need overdrive, mine runs 2400 rpm, will do it all day, and still gets decent mileage. They don't have the torque to pull at less rpm.
I think a really good setup would be a fuel injection system with two small throttle bodys, each feeding 3 cylinders. With one center mount unit, the outer cylinder will run leaner just like the carburetor setups due. A off the shelf dual intake would be a good startig point.
The 250 has a low mount water pump, so either mount the engine high, or plan on how you are going to lower the radiator. Then plan on how much tunnel you need to clear the automatic trans bell housing. I lowered the radiator and moved it forward just to have enough room for a mechanical fan, its probably 5 to 6" lower and 3-4" forward, the 250 is a longer motor. The 250 will also cost more to rebuild then a SBC, supply and demand. With a simple piston change you can boost the comression ratio from 8 to 9:1, 307 V8 chevy piston are bolt in, but must be a true flat top.
