Endomorphin analogs as potential analgesic drug

The search for novel, safe and efficient analgesics is an important but still elusive goal for medicinal chemists. Morphine and other plant-derived alkaloids have been used for centuries to alleviate strong, acute or chronic pain. However, administration of morphine is accompanied by serious side-effects, such as physical dependence, respiratory depression, constipation, decrease of blood pressure. Although in recent times a number of effective opiate derived analogs has been developed for clinical use, the ideal opiate analgesic lacking side-effects attributed to the use of morphine still remains out of reach.Opiates exert their antinociceptive activity by activation of the μ-opioid receptors. Therefore, the search for natural and synthetic ligands of this receptor has become an attractive goal. The discovery in 1997 of two endogenous ligands of the µ-opioid receptor, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), gave hope that they could be used as analgesics devoid of at least some of undesired side-effects of morphine. However, the exogenous administration of EMs as analgesics is of little therapeutic value because these peptides are quickly degraded by proteolytic enzymes and have a very limited ability to effectively penetrate the blood-brain barrier (BBB) due to their small size and hydrophilic nature. The aim of the project was the search for novel peptide analogs based on EM structure which would be stable against proteolytic enzymes and could produce strong antinociception after intravenous or oral administration.