Conformational restriction of Tyr and Phe side chains in opioid peptides: information about preferred and bioactive side-chain topology.
The side chain of Tyr and Phe was fixed into the gauche(-) or gauche(+) conformation by using the Tic Htc structures, and into the trans conformation by using an aminobenzazepine-type (Aba) structure. When incorporated into dermorphin or deltorphin II, the Tic and Htc analogues all showed a large decrease in both mu and delta affinities and activities. Fixation of Phe(3) in the trans rotamer resulted in a large increase in delta affinity in the dermorphin analogue, whereas in the [Aba(3)-Gly(4)] deltorphin II analogue, good delta affinity is maintained despite the removal of the Glu side chain. Whereas several authors propose a gauche(-) preferred conformation for the Phe(3) side chain, these results suggest a trans conformation at the delta receptor. The use of these conformationally constrained residues for evaluating the preferred solution conformation in the flexible N-terminal tripeptide Tyr-D-Ala-Phe is illustrated. The (1)H-nmr parameters--chemical shift, temperature dependence, and nuclear Overhauser effects to the D-Ala(2) methyl protons in the different analogues--provide direct evidence to confirm the proposed sandwich conformation in the native peptides.
Tourwé
D
D
Eenheid Organische Chemie, Vrije Universiteit Brussel.
Verschueren
K
K
Frycia
A
A
Davis
P
P
Porreca
F
F
Hruby
V J
VJ
Toth
G
G
Jaspers
H
H
Verheyden
P
P
Van Binst
G
G
D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D018847:Opioid Peptides / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism; D014443:Tyrosine / Q000737:chemistry*
D000701:Analgesics, Opioid; D004745:Enkephalins; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; C059567:deltorphin; C030058:dermorphin; D014443:Tyrosine; D010649:Phenylalanine; D020881:Enkephalin, D-Penicillamine (2,5)-