STRUCTURE-ACTIVITY RELATIONSHIP OF BIPHALIN - THE SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF NEW ANALOGS WITH MODIFICATIONS IN POSITION-3 AND POSITION-4

New analogues of biphalin [(Tyr-D-Ala-Gly-Phe-NH-)(2)] with modificati ons of amino acid residues in positions 3,3' and 4,4' have been synthe sized. The potency and selectivity of these analogues were evaluated b y competitive radioreceptor binding assay in the rat brain using [H-3] CTOP (mu ligand) and [H-3][p-Cl-Phe(4)]DPDPE (delta ligand) as ligands , and by bioassay in the mouse vas deferens (MVD, delta receptor assay ) and guinea pig ileum (GPI, mu receptor assay). The symmetrical subst itution of phenylalanine in positions 4 and 4' with p-fluorophenylalan ine or p-nitrophenylalanine resulted in an enhancement of the affinity at both delta and mu receptors, with some increase of the selectivity for delta opioid receptors. The analogue containing p-chlorophenylala nine in positions 4 and 4' is the most selective to the delta receptor s in this series, with a selectivity ratio about 5. The symmetrical su bstitution of the glycine-3 residue with phenylalanine resulted in a d ecrease of binding affinities and biological potencies at both mu & de lta receptors.