Synthesis and biological activities of linear and cyclic enkephalin analogues containing a Ψ (E,CH=CH) or Ψ (CH2CH2) isosteric replacement

The peptide CO–NH function was replaced by a trans carbon-carbon double bond or by a CH2–CH2 isostere in enkephalin analogues of DADLE, DCDCE–NH2 or DPDPE. In DADLE the 2-3 and the 3-4 peptide bond was modified, whereas in the cyclic analogues the Gly3-Phe4 bond was replaced by the isosteres GlyΨ (E,CH=CH)Phe [5-amino-2-(phenylmethyl)-3(E)-pentenoic acid] or GlyΨ(CH2CH2)Phe [5-amino-2-(phenylmethyl)pentanoic acid]. In general, the modification results in a drop in potency which is the largest for the flexible CH2–CH2 replacement. The Gly3Ψ (E,CH=CH)Phe4 DCDCE–NH2 analogue retains considerable potency. These results confirm the importance of the peptide function at the 2-3 and 3-4 position in enkephalin analogues for biological potency.