• Bulletin of the Korean Chemical Society
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• v.33 no.1
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• pp.261-269
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• 2012

The cyclic dimers of enkephalin were isolated as minor components during the solution synthesis of the corresponding cyclic monomers. The ratio of cyclic dimer to monomer was approximately 1:4 from the percent of yields. In the receptor binding assay of two cyclic dimmers, ($Tyr_2-C[D-Glu-Phe-gPhe]_2$ 6, $Tyr_2-C[D-Asp-Phe-gPhe-rLeu]_2$ 8), both analogs exhibited the high preference for ${\delta}$ receptor compared to monocyclic counterparts. In the nociceptive activity, both showed about 5 times less potent than the cyclic monomers. The repeated synthesis of 14-membered cyclic analog, Tyr-C[D-Glu-Phe-gPhe-D-rLeu] 14, which was known as having three distinct cis-trans isomers, gave rise to apparently different conformational analog arousing only trans isomer. In the receptor binding assay, it showed tremendously high selectivity toward ${\mu}$ receptor $({\delta}/{\mu}=160)$.

• Bulletin of the Korean Chemical Society
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• v.31 no.4
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• pp.874-880
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• 2010

A series of 13- and 14-membered cyclic enkephalin analogs based on the moderately $\mu$ selective prototype compound Tyr-C[D-$A_2bu$-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-$A_2bu$-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.

• Bulletin of the Korean Chemical Society
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• v.30 no.3
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• pp.599-607
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• 2009

A series of conjugated cyclic and linear enkephalin analogs, Tyr-c[D-A2bu-Gly-Phe-Asp(NH-X)], where X = methyl, stearyl or$ PEG_350$, and Tyr-D-Ala-Gly-Phe-Cys(S-X), where X = methyl, octyl, or farnesyl, were synthesized in solution to investigate the receptor selectivity of opioids based on Schwyzer's membrane compartment $concepts.^{5,6}$ Cyclizations of the target compounds were achieved in high yields (> 60%) employing BOP, $NaHCO_3$ in DMF despite the steric hindrance of the bulky pendant groups. In the binding assay, the hydrophobic fatty acyl conjugates retained $\mu$-receptor selectivity. The unsaturated farnesyl conjugate exhibited the increased binding affinity than the saturated stearyl conjugate for both $\mu$-and $\delta$-opioid receptors. The PEG conjugates displayed the $\delta$-receptor selectivity. The low molecular weight $PEG_350$ conjugate exhibited the increase selectivity than the high molecular weight $PEG_5000$ conjugate to the $\delta$-receptor. The results of this study support the membrane compartment concepts.