Peptide kappa opioid receptor ligands: potential for drug development

Abstract

While narcotic analgesics such as morphine, which act preferentially through mu opioid receptors, remain the gold standard in the treatment of severe pain, their use is limited by detrimental liabilities such as respiratory depression and drug dependence. Thus, there has been considerable interest in developing ligands for kappa opioid receptors (KOR) as potential analgesics and for the treatment of a variety of other disorders. These include effects mediated both by central receptors, such as antidepressant activity and a reduction in cocaine-seeking behavior, and activity resulting from the activation of peripheral receptors, such as analgesic and anti-inflammatory effects. While the vast majority of opioid receptor ligands that have progressed in preclinical development have been small molecules, significant advances have been made in recent years in identifying opioid peptide analogs that exhibit promising in vivo activity. This review will focus on possible therapeutic applications of ligands for KOR and specifically on the potential development of peptide ligands for these receptors.

Fig. 1

Nonpeptide KOR-selective ligands discussed in the text. Fedotozine, asimadoline, and ADL 10-1010 are reported to be peripherally selective

Fig. 2

Peptide KOR ligands discussed in the text. D-Amino acids in the sequences are in lower case. Dap = 2,3-diaminopropionic acid