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“Introduction At present, the treatment of severe pain relies mostly upon administration of centrally acting opiates such as morphine and its surrogates, which target μ-opioid receptors in the brain. In spite of the powerful in vivo efficacy of these drugs, their long-term use is limited by a number of well-known side-effects, MM-102 nmr including tolerance, physical

dependence, respiratory depression, and diverse gastrointestinal effects. Discovery of endogenous μ-opioid receptor ligands, endomorphin-1 (EM-1, Tyr-Pro-Trp-Phe-NH2), and endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) more than a decade ago (Zadina et al., 1997) initiated extensive studies on the possible use of these peptides as analgesics instead of morphine. EMs exhibit outstanding potencies towards both, acute and chronic neuropathic pain, as was demonstrated in rodents in various types of pain tests (Narita et al., 1999; Horvath et al., 1999; Horvath, 2000; Przewłocki and Przewłocka, 2001; Grass et al., 2002). Furthermore, potentially advantageous pharmacological properties of EMs are the possible dissociation of analgesic and rewarding effects in Protein kinase N1 the rat (Wilson et al., 2000) and the moderate respiratory depression when compared with morphine (Czapla et al., 2000; Fichna et al., 2007). However, the main limitations of the use of EMs as analgesics are short duration of action and lack of activity after oral administration, both due to the poor metabolic stability of these peptides (Shane et al., 1999; Tomboly

et al., 2002). Applying chemical modifications to the structure of EMs is one strategy to obtain compounds with desired pharmacological profile. Another strategy might be increasing the level of endogenous EMs by the use of peptidase inhibitors. The enzyme which is primarily involved in the first cleavage step of EMs is a serine peptidase, dipeptidyl peptidase IV (DPP IV), which liberates Tyr–Pro dipeptides from amino terminus of EMs (Mentlein, 1999; Tomboly et al., 2002). Proline-specific aminopeptidase M (APM) further splits the obtained fragments of EMs (Sakurada et al., 2003) (Fig. 1). Fig. 1 Scheme of EM metabolism in the brain Degradation of EMs can be significantly blocked by protease inhibitors. The most often used inhibitors of DPP IV are tripeptides Ile-Pro-Ile (diprotin A) and Val-Pro-Leu (diprotin B) (Mentlein, 1999). The action of APM is inhibited by actinonin (Sugimoto-Watanabe et al., 1999; Tomboly et al., 2002). Sakurada et al.