Structure-activity relationship of biphalin. The synthesis and biological activities of new analogues with modifications in positions 3 and 4.
New analogues of biphalin [(Tyr-D-Ala-Gly-Phe-NH-)2] with modifications of amino acid residues in positions 3,3' and 4,4' have been synthesized. The potency and selectivity of these analogues were evaluated by competitive radioreceptor binding assay in the rat brain using [3H]CTOP (mu ligand) and [3H][p-Cl-Phe4]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 substitution of phenylalanine in positions 4 and 4' with p-fluorophenylalanine 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-chlorophenylalanine in positions 4 and 4' is the most selective to the delta receptors in this series, with a selectivity ratio about 5. The symmetrical substitution of the glycine-3 residue with phenylalanine resulted in a decrease of binding affinities and biological potencies at both mu & delta receptors.
Misicka
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A
Department of Chemistry, University of Arizona, Tucson 85721, USA.
Lipkowski
A W
AW
Horvath
R
R
Davis
P
P
Porreca
F
F
Yamamura
H I
HI
Hruby
V J
VJ
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000378:metabolism
D000700:Analgesics; D004745:Enkephalins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D013004:Somatostatin; C053673:biphalin; D020881:Enkephalin, D-Penicillamine (2,5)-