My "always" gun is an S&W 340Sc, loaded with 145 grain .357 Silvertips. I put on a set of Crimson Trace grips that covers the backstrap with rubber, so it's merely unpleasant - rather than painful - to shoot. At least for a few cylinders . . . it's
not a good choice for an extended range session with .357's.
I carry it in a pocket holster, and it's very light indeed, without the functioning problems that are endemic around small autos. (A year or two back
American Rifleman tested a large selection of, IIRC, .380 autos - all but ONE experienced malfunctions during the testing.)
A good stiff belt and proper holster go a long way towards making a larger gun more comfortable. Galco makes a belt with a leather face and hard rubber backing that won't sag, and the Milt Sparks Versa-Max II is about as comforable as an IWB holster will get; I have one for a 1911, and it works nicely for my BHP.