Pharmacological Properties of Novel Cyclic Pentapeptides with µ-opioid Receptor Agonist Activity

Title:Pharmacological Properties of Novel Cyclic Pentapeptides with µ-opioid Receptor Agonist Activity

Volume: 10 Issue: 2

Author(s): Renata Perlikowska, Justyna Piekielna, Jakub Fichna, Jean Claude do-Rego, Geza Toth, Tomasz Janecki and Anna Janecka

Affiliation:

Keywords: Binding studies, µ-, δ- opioid receptor, hot-plate test, solid phase peptide synthesis, blood-brain barrier, lipophilicity.

Abstract: In our previous paper we have reported the synthesis and biological activity of a cyclic analog, Tyr-c(D-Lys- Phe-Phe-Asp)-NH₂, based on endomorphin-2 (EM-2) structure. This analog displayed high affinity for the µ-opioid receptor, was much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) injection. Even more importantly, the cyclic analog elicited weak analgesia also after peripheral administration, giving evidence that it was able to cross, at least to some extent, the blood-brain barrier (BBB). Here we describe further modifications of this analog aimed at enhancing brain delivery by increasing lipophilicity. Two new cyclic pentapeptides, Tyr-c(D-Lys-D-1-Nal-Phe-Asp)-NH₂ and Tyr-c(D-Lys-D-2-Nal-Phe-Asp)-NH₂ (where 1-Nal=1- naphthyl-3-alanine, 2-Nal=2-naphthyl-3-alanine) were synthesized and evaluated in biological assays. Both analogs showed high µ-opioid receptor affinity and agonist activity and were stable in the rat brain homogenates. Unfortunately, the increase of lipophilicity was achieved at the expense of water solubility. The analog with D-2-Nal residue showed strong analgesic effect when given i.c.v. but could not be tested after intravenous (i.v.) administration where higher concentrations of the compound are required. However, this analog showed inhibitory effect on gastrointestinal (GI) motility in vivo, providing an interesting approach to the development of peripherally restricted agents that could be useful for studying gastrointestinal disorders in animal models.

Cite this article as:

Perlikowska Renata, Piekielna Justyna, Fichna Jakub, do-Rego Claude Jean, Toth Geza, Janecki Tomasz and Janecka Anna, Pharmacological Properties of Novel Cyclic Pentapeptides with µ-opioid Receptor Agonist Activity, Medicinal Chemistry 2014; 10 (2) . https://dx.doi.org/10.2174/157340641002140131161135