Synthesis of Novel Biologically Active Peptide Analogues that are Agonists at Opioid Receptors and Antagonists at Cholecystokinin Receptors

by Wooden, Ekaphol.

From genomics, we know 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. The “system changes” that occurs must be considered in any treatment for the disease, such 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 was recently introduced in our group. In this new approach single peptide molecules are designed to interact with multiple receptor targets. For the treatment of pain, a series of linear and cyclic peptides were designed by R. S. Agnes based on the overlapping pharmacophores of opioid and CCK ligands. The opioid/CCK analogues were synthesized and evaluated for their biological activities. Several of the opioid/CCK analogues were found to simultaneously interact with opioid receptors as agonists and CCK receptors as antagonists. The lead compounds have been tested in several pain models and were found to be promising in the treatment of neuropathic pain. This study further modifies the RSA analogues to improve on the bioassays of the previous peptides. 8