Fig. 17.9 The calcium channel blocker nifedipine 17.8 contains multiple rotatable bonds. The phenyl ring can coincide with a plane of the dihydropyridine ring or they orient perpendicular to one another. To distinguish between these possibilities, lactones with different ring size 17.9 were synthesized and their crystal structures were determined. The phenyl ring lies almost parallel to the dihydropyridine ring (α ≈ 0°) in the compound with the six-membered-ring lactone (orange). Upon increasing the ring size, the angle between the two rings grows so that a perpendicular orientation (α ≈ 80°) is achieved in the twelve-membered-ring derivative (green). The biological activity increases from virtually inactive, as in the six-membered ring, to almost five orders of magnitude higher for the twelve-membered-ring derivative. The bioactive conformation of nifedipine (gray) therefore requires a perpendicular orientation of the two rings.