Newly discovered stereochemical requirements in the side-chain conformation of delta opioid agonists for recognizing opioid delta receptors.
Topographic design of peptide ligands using specialized topographically constrained amino acids can provide new insights into the stereochemical requirements for delta opioid receptors. A highly constrained tyrosine derivative, (2S,3S)-beta-methyl-2',6'-dimethyltyrosine [(2S,3S)-TMT], was prepared by asymmetric synthesis and incorporated in [D-Pen2,D-Pen5] enkephalin (delta 1) and Deltorphin I (delta 2). The results of binding assays and bioassays showed that the two analogues (3 and 4) acted very differently at delta opioid receptors. Further pharmacological evaluations suggested that they actually interact primarily with the delta 1 and delta 2 receptor subtypes, respectively. These results, and conformational studies using NMR and computer-assisted modeling, provided insights into the different stereochemical requirements for these two delta opioid ligands to recognize the delta opioid receptor and its subtypes.
Qian
X
X
Department of Chemistry, University of Arizona, Tucson 85721.
Kövér
K E
KE
Shenderovich
M D
MD
Lou
B S
BS
Misicka
A
A
Zalewska
T
T
Horváth
R
R
Davis
P
P
Bilsky
E J
EJ
Porreca
F
F
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000737:chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008781:Methyltyrosines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D004745:Enkephalins; D008781:Methyltyrosines; D009842:Oligopeptides; D010455:Peptides; D017465:Receptors, Opioid, delta; C060208:deltorphin I, Ala(2)-; C088153:2',6'-dimethyl-beta-methyltyrosine; D020881:Enkephalin, D-Penicillamine (2,5)-