Novel Bifunctional Ligands For Neuropathic Pain: Design and Synthesis of Overlapping Pharmacophores of Opioid and Melanocortin Ligands

摘要

Biologically many disease states lead to changes in expressed proteins. Therefore, "system changes" that occur must be considered in any treatment for the disease. This new approach to drug design and discovery would be particularly applicable to the diseases that involve adaptive changes in the central nervous system, such as neuropathic pain. There is growing evidence that drugs behave differently in pathological states than in normal states, thus preventing their effectiveness in pathological disease states. Therefore, a new paradigm for drug design is needed. In recent years, the melanocortin-4 receptor (MC4R) found in the spinal cord and CNS has received growing attention as a therapeutic target. MC4R based agonist ligands produce anti-opioid effects, and researchers have shown that an antagonist of the MC4R can produce pronounced anti-allodynic effect. Opioid receptors have been the central and most efficacious targets sought after for relieving neuropathic pain. In our new approach, single peptide molecules are designed to interact with opioid receptors as an agonist, and as an antagonist at the MC4 receptor. For the treatment of pain, a series of linear and cyclic peptides based on the overlapping pharmacophores of endogenous melanocyte stimulating hormone and opioid ligands are designed through computational aided molecular modeling and synthesized. Throughout the studies the opioid pharmacophore is maintained towards the N-terminal while melanocortin pharmacophore is maintained towards the C-terminal. Cyclization of peptides has been the central synthetic feature in designing the bifunctional ligands. The use of microwave has been shown to be very efficient in cyclizing the peptides. Solvent, reagent, power and temperature conditions are established for the microwave application in aiding the macromolecules for cyclizing their side chain termini.