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dc.contributor.authorBrice-Tutt, Ariana C.
dc.contributor.authorSenadheera, Sanjeewa N.
dc.contributor.authorGanno, Michelle L.
dc.contributor.authorEans, Shainnel O.
dc.contributor.authorKhaliq, Tanvir
dc.contributor.authorMurray, Thomas F.
dc.contributor.authorMcLaughlin, Jay P.
dc.contributor.authorAldrich, Jane V.
dc.identifier.citationBrice-Tutt, A. C., Senadheera, S. N., Ganno, M. L., Eans, S. O., Khaliq, T., Murray, T. F., McLaughlin, J. P., & Aldrich, J. V. (2020). Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles. Molecules (Basel, Switzerland), 25(17), 3999.
dc.descriptionThis work is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.description.abstractThe macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.en_US
dc.description.sponsorshipNational Institute on Drug Abuse (R01 DA18832)en_US
dc.description.sponsorshipNational Institute on Drug Abuse (R01 DA032928)en_US
dc.rights© 2020 by the authors. Licensee MDPI, Basel, Switzerland.en_US
dc.subjectOpioid peptideen_US
dc.subjectMacrocyclic tetrapeptideen_US
dc.subjectMultifunctional ligandsen_US
dc.subjectStructure-activity relationshipsen_US
dc.subjectKappa opioid receptoren_US
dc.subjectDelta opioid receptoren_US
dc.subjectOpioid liabilitiesen_US
dc.titlePhenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profilesen_US
kusw.kuauthorSenadheera, Sanjeewa N.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer Sherpa Romeo 11/10/2020:

Molecules [Open panel below]Publication Information TitleMolecules [English] ISSNsElectronic: 1420-3049 URL PublishersMDPI [Commercial Publisher] DOAJ Listing Requires APCYes [Data provided by DOAJ] [Open panel below]Publisher Policy Open Access pathways permitted by this journal's policy are listed below by article version. Click on a pathway for a more detailed view.

Published Version NoneCC BYPMC Any Repository, Journal Website, +1 OA PublishingThis pathway includes Open Access publishing EmbargoNo Embargo LicenceCC BY 4.0 Copyright OwnerAuthors Publisher DepositPubMed Central Location Any Repository Named Repository (PubMed Central) Journal Website ConditionsPublished source must be acknowledged with citation NotesAuthors are encouraged to submit their published articles to institutional repositories
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Except where otherwise noted, this item's license is described as: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.