A. Bocheva et al.
synthesis of enantiopure 2-aminocyclohexane carboxylic acids.
Tetrahedron: Asymm 15:2173–2178
Chen Y, Barkley MD (1998) Toward understanding tryptophan
fluorescence in proteins. Biochem 37:9976–9982
Cole CD (1994) Recent stereoselective synthetic approaches to
Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 with the same residues.
Substitution with (S)-2-(1-methyl-1H-indol-3-yl)propionic
residue had the more pronounced analgesic effect com-
pared
to
(S)-2-(5-methoxy-1H-indol-3-yl)propionic
b-amino acids. Tetrahedron 50:9517–9958
residue.
Dooley CT, Chung NN, Shiller PW, Houghten RA (1993) Acetalins:
opioid receptor antagonists determined through the use of
synthetic peptide combinatorial libraries. Proc Natl Acad Sci
90:10911
Dooley CT, Spaeth CG, Berzetei-Gurske IP, Craymer K, Adapa ID,
Brandt SR, Houghten RA, Toll L (1997) Binding and in vitro
activities of peptides with high affinity for the nociceptin/Orphanin
FQ receptor, ORL1. J Pharmacol Exp Ther 283:735–741
Gademann K, Hintermann T, Scheiber JV (1999) Beta-peptides:
twisting and turning. Curr Med Chem 6:905–925
Guerrini R, Calo’ G, Bigoni R, Rizzi A, Varani K, Toth G, Gessi S,
Hashiba E, Hashimoto Y, Lambert DG, Borea PA, Tomatis R,
Salvadori S, Regoli D (2000) Further studies on nociceptin-
related peptides: discovery of a new chemical template with
antagonist activity on the nociceptin receptor. J Med Chem
43:2805–2813
Juaristi E (1997) Enantioselective synthesis of b-aminoacids. Wiley-
VLH John Wiley and Sons, New-York, pp 1–66
Kasakov L, Nashar M, Naydenova E, Vezenkov L, Vlaskovska M
(2010) In vitro studies of the activity of newly sinthesized
nociceptin/orphanin FQ receptor ligand analogues. Protein Pept
Lett 17:616–620
Kuhl A, Hahn MG, Dumic M, Mittendorf J (2005) Alicyclic beta-
amino acids in medicinal chemistry. Amino Acids 29:89–100
Miller A, Martin SF (2007) Concise, enantioselective total synthesis
of (-)-alstonerine. Org Lett 9:1113–1116
Naydenova E, Todorov P (2011) Nociceptin/Orphanin (N/OFQ)
analogues: chemistry and biology. J UCTM 46:333–348
Naydenova E, Todorov P, Mateeva P, Zamfirova R, Pavlov N,
Todorov S (2010) Synthesis and biological activity of novel
small peptides with aminophosphonates moiety as NOP receptor
ligands. Amino Acids 39:1537–1543
JTC801 injection led to a significant decrease the pain
thresholds of referent substances and analogues 1, 2 and 4
and a significant decrease in HP-latencies of all the
investigated compounds. Interestingly, analogue 3 that
represents a substitution in 5th position of a template
known to be a NOP-receptors agonist, maintained on the
10th min a still manifest analgesic effect compared to
controls and both the referents estimated by PP- but not the
HP-test.
Naloxone injection abolished the analgesic effect of
all the substances investigated established by both PP-
and HP- tests. Interestingly, the more pronounced
decrease both in pain threshold and HP-latency was
observed after application of analogue 4 that represents a
substitution in a template known to be a l-receptor
antagonist.
In conclusion it may be stated that hexapeptides con-
taining b2-tryptophan analogues expressed analgesic
activity through both NOP- and opioid receptors. Addi-
tional investigation of mechanisms of action would be
interesting to ascertain the biological activity in respect to
structural changes in the native templates.
Acknowledgments The study was supported by Grant DTK 02/61
of the National Research Fund, Sofia, Bulgaria.
Conflict of interest The authors declare that they have no conflict
of interest.
Pavlov N, Gilles P, Didierjean C, Wenger E, Naydenova E, Martinez
2
`
J, Calmes M (2011) Asymmetric synthesis of b -tryptophan
analogues via Friedel-Crafts alkylation of indoles with a chiral
nitroacrylate. J Org Chem 76:6116–6124
Vezenkov L, Zhivkova V, Naydenova E (2006) Desin and synthesis
of new analogues of the nociceptin/orphanin FQ receptor ligands
Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 and Ac-Arg-Tyr-Tyr-Arg-
lle-Lys-NH2. Bull Chem Comm 38:64–66
Wollemann M, Benyhe S, Simon J (1993) The kappa-opioid receptor:
evidence for the different subtypes. Life Sci 52:599–611
Zaveri N (2003) Peptide and nonpeptide ligands for the nociceptin/
orphanin FQ receptor ORL1: research tools and potential
therapeutic agents. Life Sci 73:663–678
References
Ambo A, Kohara H, Kawano S, Sasaki Y (2007) Opioid receptor-like
1 (ORL1) receptor binding and the biological properties of Ac-
Arg-Tyr-Tyr-Arg-Ile-Arg-NH2 and its analogs. J Pept Sci 13:672
`
Calmes M, Didierjean C, Martinez J, Songis O (2005) (R)-(4-
(Benzyloxycarbonylphenyl)-3-hydroxy-4,4-dimethyl-2-
pyrrolidinone)acrylate derivative as a chiral dienophile for the
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