Enkephalin analogs as systemically active antinociceptive agents: O- and N-alkylated derivatives of the dipeptide amide L-2,6-dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamide.
A number of O- and N-alkylated derivatives of the antinociceptive, orally active, mu-opioid-selective truncated enkephalin analog L-2,6-dimethyltyrosyl-N-(3-phenylpropyl)-D-alaninamide (2, SC-39566) were synthesized to explore the structure-activity relationships of the series. The parent molecule is quite forgiving of substitution on the tyrosyl phenolic moiety and on the alanyl nitrogen. The tyrosyl and (phenylpropyl)amide NH sites, however, appear to be critical to interactions with the receptor, for even modest changes at these sites cause great loss of binding potency.
Pitzele
B S
BS
Department of Chemistry, Searle, Skokie, Illinois 60077.
Hamilton
R W
RW
Kudla
K D
KD
Tsymbalov
S
S
Stapelfeld
A
A
Savage
M A
MA
Clare
M
M
Hammond
D L
DL
Hansen
D W
DW
D000478:Alkylation; D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D004151:Dipeptides; D004745:Enkephalins; D011957:Receptors, Opioid; C072400:2,6-dimethyltyrosyl-N-(3-phenylpropyl)alaninamide