Structure-Activity Relationships of 13-and 14-Membered Cyclic Partial Retro-Inverso Pentapeptides Related to Enkephalin

Title
Structure-Activity Relationships of 13-and 14-Membered Cyclic Partial Retro-Inverso Pentapeptides Related to Enkephalin
Author(s)
홍남주
Keywords
RECEPTOR SELECTIVITY; BIOLOGICAL-ACTIVITY; MU-RECEPTOR; CONFORMATIONAL-ANALYSIS; COMPUTER-SIMULATIONS; ANALGESIC ACTIVITY; BINDING-AFFINITY; OPIOID RECEPTORS; MODIFIED ANALOGS; PEPTIDE ANALOGS
Issue Date
201004
Publisher
KOREAN CHEMICAL SOC
Citation
BULLETIN OF THE KOREAN CHEMICAL SOCIETY, v.31, no.4, pp.874 - 880
Abstract
A series of 13- and 14-membered cyclic enkephalin analogs based on the moderately mu selective prototype compound Tyr-C[D-A(2)bu-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 mu and delta opioid receptors The substitution of hydrophobic Leu(5) with hydrophilic Asp(5) derivatives led to Tyr-C[D-A(2)bu-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 mu and delta receptors The substitution of Phe(3) with Gly(3) led to Tyr-C[D-Glu-Gly-gPhe-rLeu] 3 and Tyr-C[D-Glu-Gly-gPhe-D-rLeu] 4, the peptides with large affinity losses at mu receptors, indicating the critical role of phenyl ring of Phe(3) for mu 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 mu and delta 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 Leu(5) on the receptor selectivity, regardless of chirality and ring size, all cyclic diastereomers displayed marked mu selectivity with low potencies at the delta receptor The retro-inverso analogs display similar or more active at mu receptor, but less active at delta receptor than the parent analogs
URI
http://hdl.handle.net/YU.REPOSITORY/22629http://dx.doi.org/10.5012/bkcs.2010.31.04.874
ISSN
0253-2964
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