New paradigm for drug design: Design and synthesis of novel biologically active peptides that are agonists at opioid receptors and antagonists at cholecystokinin receptors.

摘要

We now know from genomics that many disease states lead to changes in expressed proteins (adaptation/plasticity). Therefore, drug design and discovery based on normal states and single targets often is inadequate or even counter-indicated. Therefore, the “system changes” that have occurred must be considered in any treatment for the disease. Such “systems changes” are clearly evident in neuropathic pain where opioids can actually heighten pain. In these pain states there are increased levels of neurotransmitters such as cholecystokinin (CCK) in which both the peptides and their receptors are increased in pain states.; To effectively treat diseases involving “systems changes” a new paradigm for the design of compounds was proposed. In this new approach single peptide or peptidomimetic molecules are designed to interact with multiple receptor targets. For the treatment of pain, a series of linear and cyclic peptides and peptidomimetics were designed based on the overlapping pharmacophores of opioid and CCK ligands. The CCK/opioid analogues were synthesized and evaluated for their biological activities. Several of the CCK/opioid analogues were found to simultaneously interact with opioid receptors as agonists and CCK receptors as antagonists. In addition, the lead compounds have been tested in several pain models and were found to be promising in the treatment of neuropathic pain. Further, the structure-activity relationships of these novel peptides have provided new insights into the requirements for binding and bioactivity at opioid and CCK receptors, as well as the overlapping pharmacophores of CCK and enkephalin.