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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 31, Number 4
BKCSDE 31(4)
April 20, 2010 

Structure-Activity Relationships of 13- and 14-Membered Cyclic Partial Retro-Inverso Pentapeptides Related to Enkephalin
Nam Joo Hong
Cyclic-enkephalin, Synthesis, Bioactivity
A series of 13- and 14-membered cyclic enkephalin analogs based on the moderately 關 selective prototype compound Tyr-C[D-A2bu-Gly-Phe-Leu] 8a were synthesized to investigate the structure-activity relationship. The modifications of sequence were mainly focused on two positions 3 and 5, critical for the selective recognition for 關 and 灌 opioid receptors. The substitution of hydrophobic Leu5 with hydrophilic Asp5 derivatives led to Tyr-C[D-A2bu-Gly-Phe- Asp(N-Me)] 7 and Tyr-C[D-Glu-Phe-gPhe-rAsp(O-Me)] 5, the peptides with a large affinity losses at both 關 and 灌 receptors. The substitution of Phe3 with Gly3 led to Tyr-C[D-Glu-Gly-gPhe-rLeu] 3 and Tyr-C[D-Glu-Gly-gPhe-DrLeu] 4, the peptides with large affinity losses at 關 receptors, indicating the critical role of phenyl ring of Phe3 for 關 receptor affinities. One atom reduction of the ring size from 14-membered analogs Tyr-C[D-Glu-Phe-gPhe-(L and D)- rLeu] 6a, 6b to 13-membered analogs Tyr-C[D-Asp-Phe-gPhe-(L and D)-rLeu] 1, 2 reduced the affinity at both 關 and 灌 receptors, but increased the potency in the nociceptive assay, indicating the ring constrain is attributed to high nociceptive potency of the analogs. For the influence of D- or L-chirality of Leu5 on the receptor selectivity, regardless of chirality and ring size, all cyclic diastereomers displayed marked 關 selectivity with low potencies at the 灌 receptor. The retroinverso analogs display similar or more active at 關 receptor, but less active at 灌 receptor than the parent analogs.
874 - 880
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