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

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 asse...

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Bibliographic Details
Published in:	British journal of pharmacology Vol. 171; no. 13; pp. 3212 - 3222
Main Authors:	Aldrich, J V, Senadheera, S N, Ross, N C, Reilley, K A, Ganno, M L, Eans, S E, Murray, T F, McLaughlin, J P
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-07-2014
Subjects:	Alanine - chemistry Amino Acids - chemistry analgesic Analgesics, Opioid - chemical synthesis Analgesics, Opioid - chemistry Analgesics, Opioid - pharmacology Animals Behavior, Animal - drug effects CHO Cells CJ‐15,208 Cocaine - administration & dosage cocaine reinstatement Conditioning (Psychology) - drug effects Cricetulus Drug-Seeking Behavior - drug effects macrocyclic peptide Male Mice Mice, Inbred C57BL Narcotic Antagonists - chemical synthesis Narcotic Antagonists - chemistry Narcotic Antagonists - pharmacology Peptides, Cyclic - chemical synthesis Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Rats Receptors, Opioid, kappa - agonists Receptors, Opioid, kappa - antagonists & inhibitors Receptors, Opioid, mu - antagonists & inhibitors Research Papers Stress, Psychological - prevention & control Time Factors κ opioid receptor antagonist κ opioid receptor antagonist macrocyclic peptide analgesic CJ-15,208 cocaine reinstatement
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: The Scripps Research Institute, Jupiter, FL, USA.
ISSN:	0007-1188 1476-5381
DOI:	10.1111/bph.12664