Synthesis and analgesic effects of novel β2-tryptophan hexapeptide analogs

Abstract

Aiming to develop more potent analgesic substances a new series of hexapeptides containing β(2)-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists-naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β(2)-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH2) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.

Synthesis and Biological Activity of Small Peptides as NOP and Opioid Receptors’ Ligands

“…With a view to developing ligands with more potent analgesic activity and lower enzymatic degradation, a new series of hexapeptides containing β 2 -tryptophan analogues in positions 4 and 5, based on the templates Ac-Arg-Phe-Met-Trp-Met-Lys-NH 2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH 2 (highly potent and selective NOP receptor agonist), have been synthesized and biological evaluated (Bocheva et al, 2013;Zamfirova et al, 2013). The mechanisms of peptides' action were attempted using naloxone (an opioid antagonist) and JTC-801 (a NOP receptor antagonist).…”

“…The ligands were obtained using various design strategies, including substitution of natural and nonproteinogenic amino acids, conformational restriction, and the bivalent ligand approach (Wollemann, Benyhe, & Simon, 1993). As a part of our research, the synthesis, the characterization, and the biological activity of recently synthesized series of small peptides with aminophosphonates moiety and β-tryptophan analogues as NOP receptor ligands are described (Bocheva et al, 2013;Naydenova, Pavlov, Todorov, Dzhambazova, & Bocheva, 2011;Naydenova, Todorov, Mateeva, et al, 2010;Zamfirova et al, 2013).…”

Alkaliptosis: a new weapon for cancer therapy

“…JTC801 has been shown to be a selective antagonist for opioid-related nociceptin receptor 1 (OPRL1), a nociceptin receptor distributed throughout the brain [27]. Although it is important for JTC801-induced analgesic function to reduce pain and anxiety [28][29][30], OPRL1 seems to be unimportant for JTC801-induced alkaliptosis [18]. Certain human tumor cell lines do not express OPRL1 but still are sensitive to alkaliptosis.…”