Our Research

New Approaches to Understanding and Relieving Pain

The focus of this research group is the use of mixture-based synthetic combinatorial libraries as research tools for the identification of new receptor ligands. Development of opioid compounds with high specificity for each of the different opioid receptor types (m, d, k) and subtypes continues to be an important goal in opioid pharmacology.

All three receptor types possess analgesic properties; however, the type of pain inhibited as well as secondary functions have been shown to differ among the three receptor types. The m receptor has generally been regarded as the receptor type associated with pain relief. Undesired effects mediated by the m receptor include respiratory depression and physical dependence.

The d and k receptors are also associated with pain relief, and are thought to have less potential for addiction. Such differences in receptor functions encourage the search for pharmaceutical candidates that produce analgesia without deleterious side effects. We have identified active k compounds that are now in clinical trials in collaboration with a pharmaceutical company.

Opioid Receptors

In the first practical case study of the use of combinatorial libraries for the identification of receptor ligands, a hexapeptide library containing over 50 million different peptides was screened in an opioid assay and yielded sequences that corresponded to the naturally occurring opioid peptides, methionine and leucine enkephalin. A number of other m-selective ligands have been identified that have little or no resemblance to the naturally occurring opioid peptides.

Screening of an N-acetylated library yielded new opioid antagonists, termed the Acetalins, and the peptide Ac-RWIGWR-NH2, plus a peptide agonist, Ac-FRWWYM-NH2 [1]. A hexapeptide library composed entirely of D-amino acids was used to identify the peptide Ac-rfwink-NH2 [2]. The in vivo potency of Ac-rfwink-NH2 is approximately twice that of morphine. Ac-rfwink-NH2 produced pain relief equal to that of morphine following peripheral administration, indicating that this peptide readily crosses the blood-brain barrier.

Peptides selective for each of the subtypes have been identified from a single tetrapeptide library [3]. Furthermore, nonpeptide m antagonists have been identified from the screening of libraries generated through the "libraries from libraries" method.

Orphanin Receptor

Orphanin FQ, the natural ligand for a newly identified opioid related receptor, was first reported by two other laboratories in 1995. We have developed a radioreceptor binding assay for Orphanin FQ, and have screened a number of combinatorial libraries to identify new, low molecular weight ligands for this receptor [4].

Peptide, peptidomimetic and classical small molecule and heterocyclic libraries continue to be examined. Recently, we have identified low molecular weight heterocyclic compounds with antagonist activity at this receptor. Since native Orphanin FQ in vivo causes hypersensitivity to painful stimuli, a compound that can antagonize such hypersensitivity could play an important therapeutic role in pain modulation.

Key References

  1. Dooley, C.T., et al. Acetalins: Opioid receptor antagonists determined through the use of synthetic peptide combinatorial libraries. Proc. Natl. Acad. Sci. USA 90:10811-10815, 1993.
  2. Dooley, C.T., et al. An all D-amino acid opioid peptide with central analgesic activity from a combinatorial library. Science 266:2019-2022, 1994.
  3. Dooley, C.T., et al. Selective ligands for the mu, delta and kappa opioid receptors identified from a single tetrapeptide positional scanning combinatorial library. J. Biol. Chem. 273:18848-18856, 1998.
  4. Dooley, C.T., et al. Binding and in vitro activities of peptides with high affinity for the Nociceptin/Orphanin FQ receptor, ORL11. J. Pharm. Exp. Ther., 283:735-741, 1997.