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. 2007 Nov 1;50(22):5528-32.
doi: 10.1021/jm061465o. Epub 2007 Oct 10.

Development of novel enkephalin analogues that have enhanced opioid activities at both mu and delta opioid receptors

Yeon Sun Lee  1 , Ravil Petrov, Chad K Park, Shou-wu Ma, Peg Davis, Josephine Lai, Frank Porreca, Ruben Vardanyan, Victor J Hruby
Affiliations

Development of novel enkephalin analogues that have enhanced opioid activities at both mu and delta opioid receptors

Yeon Sun Lee et al. J Med Chem. .

Abstract

Enkephalin analogues with a 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed mu and delta opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety, showed very high binding affinities (0.4 nM) at mu and delta receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.

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Figures

Figure 1
Figure 1
Chemical structure of opioid analogues
Figure 2
Figure 2
Design of opioid ligands.
Scheme 1<sup>a</sup>
Scheme 1a
a (a) stepwise coupling (BOP/HOBt/NMM, DMF, rt, 2-4 h) and deprotection (TFA, 0 °C, 20 min); (b) 1N KOH, EtOH; (c) NH2-NH2, DMF, 1 day; (d) succinic anhydride, EtOAc, 1 day; (e) BOP/HOBt/NMM, DMF, 4 h; (f) TFA, 0 °C, 20 min
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