CONFORMATION AND BIOLOGICAL-ACTIVITIES OF HEXAPEPTIDES RELATED TO ENKEPHALINS - RESPECTIVE ROLES OF THE AMMONIUM AND HYDROXYL-GROUPS OF TYROSINE

In order to explore the role of the additional Arg or Tyr residue in the activity of Arg-Met-enkephalin (Arg-Met-E) and Tyr-Met-E, a series of analogs were prepared and their biological activities in the inhibition of 3H-Leu-E binding to mouse striatum or the contraction of guinea pig ileum and mouse vas deferens were analyzed. The presence of an ammonium group located on the CH.alpha. of the N-terminal aminoacid is absolutely required for activity whereas its position relative to the backbone can be somewhat modified: the presence of an OH group strictly on Tyr1 of E is an absolute requirement. NMR studies indicate that the characteristic conformation of E backbone is retained in the analogs ruling out that the observed changes in activity are related to modified conformation of this part of the molecule. A model for the interaction of enkephalins with their receptors, involving electrostatic and Van der Waals forces, is proposed.