Substrate specificity of .MU./.DELTA.-receptor on the basis of stereo-structure of enkephalin.

Enkephalin is a morphine-like pentapeptide: Tyr-Gly-Gly-Phe-Xxx, Xxx=Met or Leu. To consider the relationship between the enkephalin conformation and the opioid receptor, the crystal structures of enkephalin analogues were analyzed by the X-ray diffraction method, and two characteristic forms were observed as the fundamental conformation of enkephalin, One is the β-turn structllre and the other the antiparallelly extended dimer (ED) structure. From the NMR and CD spectral studies, it was suggested that the β-turn and ED structures of enkephalin are the most probable conformations for the binding to μ-and δ-receptors, respectively. Further, the molecular-dynamics simulations indicated that these conformation are both advantageous in energetical term. Based on the insight of the enkephalin conformation, it was attempted to convert the μ-selective morphine toward δ-affinitive ligand by the dimerization.