Alanine analogues of [D-Trp]CJ-15,208: Novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour

J. V. Aldrich, S. N. Senadheera, N. C. Ross, K. A. Reilley, M. L. Ganno, S. E. Eans, T. F. Murray, J. P. McLaughlin

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background and Purpose The novel macrocyclic peptide cyclo[Phe-D-Pro-Phe-D- Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. Experimental Approach The peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. Key Results The alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and μ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28-4.19-nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine- and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. Conclusions and Implications These unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics.

Original languageEnglish (US)
Pages (from-to)3212-3222
Number of pages11
JournalBritish Journal of Pharmacology
Volume171
Issue number13
DOIs
StatePublished - Jul 2014

All Science Journal Classification (ASJC) codes

  • Pharmacology

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