Synthesis and receptor binding analysis of dermorphin hepta‐, hexa‐ and pentapeptide analogues

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Abstract
Sixteen dermorphin analogues were synthesized and characterized for mu- and delta-opioid receptor binding properties using [3H]DAGO and [3H]DPDPE, respectively. The analogues included the following: substitutions at position 4 and/or the C-terminal residue; deletions of Gly4 or Pro6-Ser7; inclusion of Z or an acetyl group on the epsilon-amino group of Lys7; and the presence of either a C-terminal amide or free acid group. Two peptides, [Lys7-OH]- and [Lys7-NH2]dermorphin, had mu-affinities (Ki mu = 0.15-0.13 nM) and mu-selectivities (Ki delta/Ki mu = 1158-1482) higher than dermorphin (Ki mu = 0.28 nM; Ki delta/Ki mu = 295) and best fitted a one-site binding model similar to dermorphin. Significantly better (P < 0.0001) fits to a two-site binding model vs. a one-site model were observed with four dermorphin analogues: [Lys(Z)7-OH]heptapeptide, [des-Gly4(Tyr4,Pro5,Asn6-OH)]hexapeptide and two pentapeptides, [Tyr5-NH2] and [Trp4,Asn5-OH]. Our data revealed a complex binding pattern for dermorphin analogues to brain mu-receptors in which Hill coefficients less than 0.85 generally suggest heterogeneity of mu-receptors; however, only detailed analyses of the data derived from the non-linear regression fits for one- or two-components gave evidence for the possible existence of two separate [3H]DAGO binding sites. Eight of our dermorphin analogues had significantly better fits for a two-site model (P < 0.05), but only four seemed to have two distinct Ki values (P < 0.0001).