Journal of Medicinal Chemistry 2002-06-06

Endomorphin-1 analogues containing beta-proline are mu-opioid receptor agonists and display enhanced enzymatic hydrolysis resistance.

Giuliana Cardillo, Luca Gentilucci, Ahmed R Qasem, Fabio Sgarzi, Santi Spampinato

Index: J. Med. Chem. 45(12) , 2571-8, (2002)

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Abstract

In this paper we describe the synthesis and affinity toward the mu-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH(2) (1), by substituting each amino acid in turn with its homologue. The ability to bind mu-opioid receptors depends on the beta-amino acid, and in particular 4, which contains beta-L-Pro, has a K(I) in the nanomolar range. The peptides 4 and 5 are significantly more resistant to enzymatic hydrolysis than 1. The same compounds, as well as the mu-opioid receptor agonist DAMGO, produced a concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation, thus behaving as mu-opioid agonists. These features suggest that this novel class of endomorphin-1 analogues may represent suitable candidates for the in vivo investigation as potential mu-opioid receptor agonists.