Design, Synthesis And Biological Activity Characterization Of Endomorphin Analogs

Opioid agonists are the most frequently used analgesics for the relief of s-evere pain, but their usefulness is limited by a number of well known side eff-ects, including tolerance, physical dependence, respiratory depression, adverse g-astrointestinal effects, etc. Therefore, numerous analogues have been synthesize-d in attempts to develop an analgesic without the serious side effects. Recentl-y, two new peptides, endomorphin-1 and endomorphin-2, were isolated from m-ammalian brain and found to activateμ-opioid receptors with high affinity an-d selectivity. They are thought to inhibit pain without some of the undesirable side effects. However, EMs still suffers from serious limitations because of pro-blems with low bioavailability short duration of action, lack of oral activity, r-elative inability to cross the BBB into the CNS, and poor metabolic stability. Some studies found that endomorphin-1 was more active than endomorphin-2 i-n antinociceptive potencies. Herein, EM-1 was chosen as the parent compound.We ues three kind of modification approaches, including D-Ala-Gly substit-utions in position 2, Na-amidination, and C-terminal chloro-halogenation or flu-oro-halogenation,.Five new EM-1 analogues were designed and synthesized. To detect the biological activity profiles of the analogues, we done some tests, w-hich include receptor binding assessment, in vitro bioactivity assessment, metab-olic stability assessment and antinociception assessment. Both Nα-amidination a-nd D-Ala-Gly substitutions in position 2 in EM-1 caused a increase of affinity for theμ,-opioid receptor, increase of metabolic stability and antinociceptive ac-tivity, but the EM-2 analog caused a increase of metabolic stability, decrease of affinity for theμ,-opioid receptor and antinociceptive activity. Analog GAGP-C decreases drug tolerance.