Conjugates of Enkephalin Analogs: Synthesis and Discrimination of μ and δ Opioid Receptors Based on Membrane Compartment Concept

A series of conjugated cyclic and linear enkephalin analogs, Tyr-c[D-A2bu-Gly-Phe-Asp(NH-X)], where X = methyl, stearyl or PEG350, 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, NaHCO3 in DMF despite the steric hindrance of the bulky pendant groups. In the binding assay, the hydrophobic fatty acyl conjugates retained μ-receptor selectivity. The unsaturated farnesyl conjugate exhibited the increased binding affinity than the saturated stearyl conjugate for both μ-and δ-opioid receptors. The PEG conjugates displayed the δ-receptor selectivity. The low molecular weight PEG350 conjugate exhibited the increase selectivity than the high molecular weight PEG5000 conjugate to the δ-receptor. The results of this study support the membrane compartment concepts. KCI Citation Count: 5