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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010N/OFQ(1-13)NH 2 Analogues with Aminophosphonate Moiety:Synthesis and Analgesic ActivityEmilia D. Naydenova 1 , Petar T. Todorov 1 , Nikola D. Pavlov 1 ,Elena B. Dzhambazova 2 , and Adriana I. Bocheva 31 Department of Organic Chemistry, University of Chemical Technologies and Metallurgy,1756, Sofia, Bulgaria; 2 Department Physiology and Clinical Physiology, Sofia UniversitySt. Kl. Ohridski, Faculty of Medicine, 1407, Sofia, Bulgaria; 3 Department ofPathophysiology, Medical University, 1431, Sofia, BulgariaIntroductionNociceptin/orphanin FQ is a neuropeptide (heptadecapeptide: Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln) that selectively interacts with theopioid-like receptor (ORL 1 or NOP), a novel member of the opioid receptor family. It hasbeen reported that the nociceptin-NOP system modulates several biological functions,including pain transmission, stress and anxiety, learning and memory, locomotor activity,food intake [1]. N/OFQ(1-13)NH 2 is the minimal sequence maintaining the same activity asthe natural peptide nociceptin. Structure-activity studies demonstrated that N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptorligands.Pain is a frequently observed symptom of various diseases. Some of the greatestachievements in medicine in theoretical and in clinical aspect are connected with theresearch on pain and especially on the development of analgesic drugs. -Aminophosphonicacids and aminophosphonates have reached position of eminence in theresearch works intending to discover, to understand and to modify physiological processesin the living organisms. They are also a potential source of medicinal lead compounds [2].Results and DiscussionAiming to develop ligands for the NOP that possess stronger analgesic activity, a newseries of N-modified analogues of the N/OFQ(1-13)NH 2 with aminophosphonate moietywere prepared and tested for the nociceptive effects. The new analogues (Figure 1) havebeen synthesized including cyclic -aminophosphonates at position 1, using SPPS by Fmoc(9-fluorenylmethoxy-carbonyl) chemistry. The 1-[(dimethoxyphosphono) methylamino]-cycloalkanecarboxylic acids were previously prepared by our group followingKabachnik-Fields reaction [2,3].1OHO1P CH 2 NH CO N/OFQ(1-13)NH 2P CH 2 NH CO N/OFQ(1-13)NH 2 5H 3 COOHOP CH 2 NH CO N/OFQ(1-13)NH 2 2H 3 COOHO1P CH 2 NH CO N/OFQ(1-13)NH 2 3H 3 COOHOP CH 2 NH CO N/OFQ(1-13)NH 2 4H 3 COHOO1H 3 COHOH 3 COOPCH 2NHCON/OFQ(1-13)NH 26Fig. 1. N-modified analogues of N/OFQ(1-13)NH 2 with aminophosphonate moiety.486