Synthesis and Investigations of Peptidic-Non-Peptidic Bivalent Ligands for Treatment of Pain

摘要

Opioid analgesics are the mainstay for treatment of moderate to severe pain, but they still have significant disadvantages. In attempts to avoid them as well as to try to find compounds for relief of untreatable pain, our research in the last years has been devoted to the design and synthesis of new bifunctional ligands, which combine the structure of the strong opioid -Fentanyl with an adjuvant analgesic. A series of compounds - representatives of mixed peptidic-non-peptidic bivalent ligands in which the two ligands are merged into a single entity that can hit multiple targets have been synthesized. Among them are mixed μ- and δ-opioid agonists; μ-opioid agonist- δ-opioid antagonists; μ-opioid agonist-NK1 antagonists; μ-opioid agonist-MC modulators and μ-opioid agonist-COX inhibitors. Different functionalized Fentanyl derivatives like carboxy-, amino-, and hydrazino-Fentanyls have been designed and synthesized as lipophilic scaffolds with novel chemical/physical properties and with log Ps consistent with drugable properties. Entities with very high binding affinities (0.4 nM) at μ- and δ- receptors with an increased hydrophobicity were found among the novel compounds (Figure 1).