Synthesis and biological activity of novel small peptides with aminophosphonates moiety as NOP receptor ligands

Abstract

The aim of the present study was the synthesis and the biological screening of new analogs of Ac-RYYRWK-NH2, modified at the N-terminal with 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids. The four newly synthesized ligands for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) have been prepared by solid-phase peptide synthesis--Fmoc-strategy. These compounds were tested for agonistic activity in vitro on electrically stimulated smooth-muscle preparations isolated from vas deferens of Wistar rats. Our data showed that substitution of Arg at position 1 with aminophosphonates moiety decreased significantly the affinity of ligands to the NOP receptor. Furthermore, the enlargement of the cycle (with 5-8 carbon atoms) additionally diminished both the activity and the selectivity for NOP-receptor.

In vitro Antitumour Activity, Genotoxicity, and Antiproliferative Effects of Aminophosphonic Acid Diesters and their Synthetic Precursors

“…The corresponding aminophosphonate M-6 was also not toxic to this cell line (Fig. 3B), suggesting that these cells lack receptors for the two compounds (Surowiak et al, 2006;Naydenova et al, 2010). There was no difference in the actions of M-3 and M-6 on the HepG2 cell line.…”

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

“…During the last few years, new shortened analogues of nociceptin by Fmoc solid-phase method have been performed by our team (Naydenova, Todorov, Mateeva, et al, 2010;. The influence of Gly and Ala residues has been investigated through their consecutive substitution with βAla in H-Phe-Gly-Gly-Phe-Thr-βAla-NH 2 and H-Phe-Gly-Gly-Phe-Thr-Gly-βAla-NH 2 peptides.…”

“…Development of selective and highly potent peptide and nonpeptide agonist and antagonist ligands is of great importance for the understanding of the physiological and pathological roles of N/OFQ-NOP receptor system, too. Among them are N/OFQ-related peptides (Ambo, Kohara, Kawano, & Sasaki, 2007;Guerrini, Calò, et al, 2000;Naydenova, Todorov, Mateeva, et al, 2010;Guerrini, Calò, Bigoni, Rizzi, Regoli, & Salvadori, 2001;, small peptides, identified by screening of peptide combinatorial libraries (Dooley, Chung, Shiller, & Houghten, 1993;Dooley et al, 1997), and nonpeptide ligands such as Ro 64-6198 and JTC-801 (Zaveri, 2003;Zaveri, Jiang, Olsen, Polgar, & Toll, 2005). The synthesis of new NOP receptor ligands with higher affinity and lower enzymatic degradation is a primary goal of many research teams.…”

“…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).…”

<strong>Kabachnik&ndash;Fields synthesis of novel 2-oxoindolin methyl phosphonate derivatives using CAN.</strong>

“…α-aminophosphonates are among the most studied bioactive organo phosphorus derivatives and have been used as enzyme inhibitors [3], inhibitors of serine hydrolase [4], peptide mimics [5], antiviral [6], antibacterial [7], antifungal [8], anticancer [9], anti-HIV [10], antibiotics [11], herbicidal [12] etc.…”