For shits and giggles, it's funny as hell to play a zone defense in a pickup game ... you are almost guaranteed to absolutely destroy the other team if a) they are idiots and b) your team knows what they are doing.
Someone always seems to fuck it up. I'm more of a fan of full court pressing in a pick up game. All out hustle and shooting is lethal in the pick up setting.
Other than pressing, the way defensive strategy is to find the LeBron wannabe and let him jack up long twos and pull up jumpers.