Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine

Biosynthetic Short Neuropeptides: A Rational Theory Based on Experimental Results for the Missing Pain‐Relief Opioid Endomorphin Precursor Gene

“…Both peptides produce transient anti‐hyperalgesic and analgesic effects associated with an unresolved tolerance mechanism. Animal experiments in rodent models have suggested that endomorphins may reduce anxiety and depression . Endomorphin analogues that reduce respiratory depression, tolerance, abuse liability, and motor impairment have been developed for use as new analgesic drugs .…”

“…It was suggested that enzymatic conjugation of smaller peptide fragments proceeded through a comparable mechanism to that of the production of prokaryotic nonribosomal peptide; however, such a mechanism is not reported in eukaryotic cells, and thus, the proposed endomorphin de novo biosynthetic mechanism still requires more robust experimental confirmation. Endomorphins are now thought to be good candidates for pain modulation because of their high biological activity, and improvements to their metabolic stability and/or their ability to cross the blood–brain barrier are needed and well studied . All three of the previously reported precursor protein genes of opioid peptides encode multiple neuropeptides; therefore, the preproendomorphin gene would be expected to include novel bioactive peptides with potential utility for pain control.…”

“…Endomorphins are now thought to be good candidates for pain modulation because of their high biological activity,a nd improvements to their metabolic stability and/or their ability to cross the blood-brain barriera re neededa nd well studied. [7][8][9][10] All three of the previously reported precursor protein genes of opioid peptides encode multiple neuropeptides;t herefore, the preproendomorphin gene would be expectedt oi nclude novel bioactive peptides with potentialu tility for pain control. In the preceding years, we andm any researchersh ave made efforts to find the preproendomorphin genes.…”

Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics

“…Importantly, a report by Zadina et al suggested that the EM analogues could provide a gold standard pain relief mediated by selective MOR activation but with remarkably safer side effect profiles compared to those of opioids, such as morphine [121]. These authors synthesized four types of cyclized, dextro-amino acid-containing EM analogues and compared these analogues to morphine; these analogues showed remarkably improved properties in respiratory depression, motor impairment, tolerance, immune reactivity, and reward/abuse liability in rats without impairing the affinity.…”

Biomedicine: Move over, morphine

“…The hope is that these molecules will still trigger the same response as the parent compound. Zadina has identified four new analogues of endomorphin 2 , and is now preparing to take the best-performing into clinical trials. That compound, dubbed analogue 4, provides "much longer duration of analgesia" than morphine, says Zadina.…”