Cyclic enkephalin analogues containing alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid at positions 2 or 5.
Analogues of the highly potent and delta-receptor-selective enkephalins 1-4 were prepared with alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid (Apmp) replacing the beta,beta-dimethylcysteine (Pen) at positions 2 or 5. The peptides 5-8 were prepared by employing D,L-Apmp and, following oxidative cyclization, the resulting diastereomeric peptides were separated and purified by preparative high performance liquid chromatography. Compounds 7 and 8, with D- or L-Apmp substituted at position 5 are approximately 5 orders of magnitude more potent in the MVD assay than analogues 5 or 6 with D- or L-Apmp at position 2. While displaying less delta-receptor selectivity than the corresponding Pen-containing compounds, 7 and 8 are an order of magnitude more potent. All the analogues showed diminished delta-receptor selectivity in the rat brain binding assay. Compounds 7 and 8 displayed delta-receptor affinity comparable to the corresponding Pen-containing analogues.
Bryan
W M
WM
Department of Peptide Chemistry, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406-0939.
Callahan
J F
JF
Codd
E E
EE
Lemieux
C
C
Moore
M L
ML
Schiller
P W
PW
Walker
R F
RF
Huffman
W F
WF
D000603:Amino Acids, Sulfur / Q000494:pharmacology*; D000818:Animals; D004745:Enkephalins / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects; D017465:Receptors, Opioid, delta; D013329:Structure-Activity Relationship
D000603:Amino Acids, Sulfur; D004745:Enkephalins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta