Investigation of the structural parameters involved in the .mu. and .delta. opioid receptor discrimination of linear enkephalin-related peptides

Abstract

The previous rules proposed for selective recognition of .mu. and .delta. opioid receptors by modified enkephalins were investigated through an extensive structure-activity study. Thus, modifications of the sequence of TRIMU 4 (Tyr-D-Ala-Gly-NHCH(CH3)CH2CH(CH3)2, a peptide that exhibits .mu. selectivity close to that of DAGO (Tyr-D-Ala-Gly-N(Me)Phe-Gly.cntdot.ol), were performed for two positions, 2 and 4, critical for .mu. recognition. The drastic loss of potency following introduction of L-Ala or Aib in position 2 emphasizes the importance of the stereochemistry and the steric size of the X2 amino acid for optimal .mu. binding. The enhancement of the intrinsic flexibility of the C-terminal alkyl chain of TRIMU 4 through removal of a methyl group leads to TRIMU 5 (Tyr-D-Ala-Gly-NHCH2CH2CH(CH32), a peptide with a .mu. selectivity similar to that of DAGO. In contrast, introduction of an O-tert-butyl Ser2 residue increases affinity for .delta. receptors. In the hexapeptide series derived from DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr),a D-Thr2 moiety was shown to be very efficient in improving .delta. recognition and .delta. selectivity appeared also to be modulated by the nature of the sixth residue. The potencies of the 24 peptides studied to inhibit the electrically evoked contractions of the GPI of MVD are relatively well correlated with their affinities for brain .mu. or .delta. receptors labeled with [3H]DAGO or [3H]DSLET, respectively. Moreover, the analgesic potency (hot plate test) of the peptides is related to their affinity for rat brain .mu. receptors. The wide range of receptor affinities exhibited by the compounds reported here could be useful to study the physiological role of .mu. and .delta. receptors.