New Dimeric Tetrapeptide Enkephalin Analogues Hydrophilic Spacer Length and Configuration Affects Potency and Receptor Selectivity

Janusz Stępiński* a, S. William Tamb a Department of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warsaw, Poland b The DuPont Merck Pharmaceutical Company, Wilmington, DE, U.S.A. Z. Naturforsch. 49b, 407-411 (1994); received September 9,1993 Bivalent Opioids, Enkephalin Analogues, Opioid Receptor Selectivity Three new bivalent opioid peptide analogues, l,3-di-(tyrosyl-D-alanyl-glycyl-phenylalanylamido)-2-propanol, 1,4-di-(tyrosyl-D-alanyl-glycyl-phenylalanylamido)-(2 R, 3 S)-butanediol and l,4-di-(tyrosyl-D-alanyl-glycyl-phenylalanylamido)-(2i?,3i?)-butanediol, were synthesized and tested in vitro for pi, d and x receptor affinities. They were found to have potent opioid receptor binding activity. The (25,35)-butanediol bridge configuration yield­ ed selectivity and high potency for pi and x receptors, while the (2/?,37?)-butanediol bridge configuration yielded high potency and selectivity for <3 receptors. It thus appears that changes in the length and configuration of the polyhydroxyl bridge in dimeric enkephalin analogues can produce a shift in receptor selectivity profiles and therefore suggest the possibility of developing more selective drugs.