Amino Acids

, Volume 40, Issue 5, pp 1503–1511

New potent biphalin analogues containing p-fluoro-l-phenylalanine at the 4,4′ positions and non-hydrazine linkers

  • Adriano Mollica
  • Francesco Pinnen
  • Federica Feliciani
  • Azzurra Stefanucci
  • Gino Lucente
  • Peg Davis
  • Frank Porreca
  • Shou-Wu Ma
  • Josephine Lai
  • Victor J. Hruby
Original Article

DOI: 10.1007/s00726-010-0760-7

Cite this article as:
Mollica, A., Pinnen, F., Feliciani, F. et al. Amino Acids (2011) 40: 1503. doi:10.1007/s00726-010-0760-7

Abstract

We report the synthesis and the biological evaluation of two new analogues of the potent dimeric opioid peptide biphalin. The performed modification is based on the replacement of two key structural elements of the native biphalin, namely: the hydrazine bridge which joins the two palindromic moieties and the phenylalanine residues at the 4,4′ positions of the backbone. The new analogues 9 and 10 contain 1,2-phenylenediamine and piperazine, respectively, in place of the hydrazidic linker and p-fluoro-l-phenylalanine residues at 4 and 4′ positions. Binding values are: \( K_{\text{i}}^{\mu } = 0.51\,{\text{nM}} \) and \( K_{\text{i}}^{\delta } = 12.8\,{\text{nM}} \) for compound 9, \( K_{\text{i}}^{\mu } = 0.09\,{\text{nM}} \) and \( K_{\text{i}}^{\delta } = 0.11\,{\text{nM}} \) for analogue 10.

Keywords

Activity Biphalin Dimeric peptide ligands Opioid peptides Synthesis 

Abbreviations

Boc

tert-Butyloxycarbonyl

[3H]DAMGO

[d-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin

[3H]DPDPE

[3H]-c[d-Pen2, d-Pen5]enkephalin

DCM

Dichloromethane

DIPEA

N,N-Diisopropylethylamine

DMAP

4-(Dimethylamino)pyridine

DMF

N,N-Dimethyl formamide

DMSO

Dimethylsulfoxide

EDC

1-Ethyl-(3-dimethylaminopropyl)carbodiimide

GPI/LMMP

Guinea pig ileum/longitudinal muscle myenteric plexus (μ-opioid receptors)

hMOR

Human μ-opioid receptor

HOBt

1-Hydroxybenzotriazole

MVD

Mouse vas deferens (δ-opioid receptors)

NMM

N-Methyl morpholine

rDOR

Rat δ-opioid receptor

TEA

Triethylamine

TFA

Trifluoroacetic acid

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Adriano Mollica
    • 1
  • Francesco Pinnen
    • 1
  • Federica Feliciani
    • 1
  • Azzurra Stefanucci
    • 1
  • Gino Lucente
    • 2
  • Peg Davis
    • 3
  • Frank Porreca
    • 3
  • Shou-Wu Ma
    • 3
  • Josephine Lai
    • 3
  • Victor J. Hruby
    • 4
  1. 1.Dipartimento di Scienze del FarmacoUniversità di Chieti-Pescara “G. d’Annunzio”ChietiItaly
  2. 2.Istituto di Chimica Biomolecolare (CNR) c/o Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza”Università di RomaRomeItaly
  3. 3.Department of PharmacologyUniversity of ArizonaTucsonUSA
  4. 4.Department of Chemistry and BiochemistryUniversity of ArizonaTucsonUSA

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