COMPETITIVE-INHIBITION OF LIPOLYTIC ENZYMES .10. FURTHER DELINEATION OF THE ACTIVE-SITE OF PANCREATIC PHOSPHOLIPASES A(2) FROM PIG, OX AND HORSE BY COMPARING THE INHIBITORY POWER OF A NUMBER OF (R)-2-ACYLAMINOPHOSPHOLIPID ANALOGS

Two series of (R)-phospholipid analogues, each containing a n-propyl g roup at the C-1 position and various acylamino functions at the C-2 po sition have been synthesized and their inhibitory properties towards t hree mammalian pancreatic phospholipases A(2) have been determined. Th e members of the first series of analogues all contained the zwitter-i onic phosphocholine headgroup which in the second series was replaced by the anionic phosphoglycol function. In the saturated 2-acylamino ph ospholipids the length of the acyl chain ranged from 8 to 18 carbon at oms. The unsaturated 2-acylamino analogues possessed a chain length of 11 or 18 carbon atoms and contained one, two, three or four double bo nds. For inhibitors with a saturated acylamino group, the phospholipas es A(2) from pig, ox and horse show a sharp optimum in inhibitory powe r Z for an acyl chain length of 10 carbon atoms. The inhibitory behavi our of the unsaturated acylamino analogues is more complex: both the z witter-ionic and the anionic inhibitors demonstrate an increase in Z w ith an increasing number of cis-double bonds but the degree of improve ment is dependent on the position of the double bonds. Subsequently th e influence of polar groups at carbon position 12 of the dodecanoylami no phospholipids on Z was analyzed. Substitution of the terminal methy l group by an OH-function lowers the inhibitory potency of the three e nzymes by a factor of 4 to 5 both in the phosphocholine and phosphogly col series. Replacement of the methyl group by potentially charged fun ctions (-NH2, -COOH) resulted in a complete loss of inhibitory propert ies. Blocking of the amino group and carboxyl function by t-butyloxyca rbonylation and esterification, respectively, fully restored the inhib itory power. Finally we investigated how changes in the polar headgrou p and the presence of aromatic rings at the C-1 or C-2 position influe nced the inhibitory potency of the analogues.