Synthesis and biological properties of beta-MePhe3 analogues of deltorphin I and dermenkephalin: influence of biased chi 1 Phe3 residues on peptide recognition for delta-opioid receptors.
Using the method of conformational constraint, we have designed and synthesized analogues of deltorphin I and dermenkephalin containing each of the four stereoisomers (2S,3S; 2S,3R; 2R,3S; 2R,3R) of the unusual amino acid beta-methylphenylalanine in position three. The potency and selectivity of these analogues were evaluated by radioreceptor binding assays in the rat brain using [3H]CTOP (mu-ligand) and[3H]p-C1Phe4]DPDPE (delta-ligand), and by bioassay using the mouse vas deferens (delta-receptor assay) and guinea pig ileum (mu-receptor assay) assays. The substitution of a beta-MePhe for Phe3 in deltorphin I and dermenkephalin has a large and variable effect on the bioactivities of the synthesized analogues. The synthesized analogues are somewhat less potent than the native peptides. Both [(2S,3R)-beta-MePhe3]deltorphin and [(2S,3R)-beta-MePhe3] dermenkephalin are more selective, however, and interact essentially specifically with the receptor in the binding assays and bioassays. The bioassay data in vitro of the synthesized analogues of deltorphin I and dermenkephalin follow the same general trends as the receptor binding data. These results demonstrate that topographical modifications of the side-chain conformation of critical structural moieties in a ligand can significantly modulate both the potency and receptor selectivity for ligands that have multiple sites of biological activity, and they illustrate that this approach has general application to peptide and peptidomimetic ligand design.
Misicka
A
A
Department of Chemistry, University of Arizona, Tucson, USA.
Cavagnero
S
S
Horvath
R
R
Davis
P
P
Porreca
F
F
Yamamura
H I
HI
Hruby
V J
VJ
D000613:Aminobutyrates / Q000737:chemistry*; D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects; D004558:Electric Stimulation; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D013237:Stereoisomerism
D000613:Aminobutyrates; D000701:Analgesics, Opioid; D004745:Enkephalins; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; C059567:deltorphin; C060208:deltorphin I, Ala(2)-; C010535:2-amino-3-phenylbutanoic acid; D020881:Enkephalin, D-Penicillamine (2,5)-