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We hypothesized that the L\u2010 and D\u2010Trp isomers of CJ\u201015,208, a natural cyclic tetrapeptide reported to be a \u03ba\u2010receptor antagonist<jats:italic>in vitro<\/jats:italic>, would demonstrate short\u2010acting, dose\u2010dependent antagonism<jats:italic>in vivo<\/jats:italic>, preventing reinstatement of cocaine\u2010seeking behaviour.<\/jats:p><\/jats:sec><jats:sec><jats:title>EXPERIMENTAL APPROACH<\/jats:title><jats:p>Affinity, selectivity and efficacy of the L\u2010Trp and D\u2010Trp isomers for opioid receptors were assessed<jats:italic>in vitro<\/jats:italic>in radioligand and GTP\u03b3S binding assays. Opioid receptor agonist and antagonist activities were characterized<jats:italic>in vivo<\/jats:italic>following i.c.v. administration with the 55\u00b0C warm water tail\u2010withdrawal assay. The D\u2010Trp isomer, which demonstrated primarily \u03ba\u2010receptor selective antagonist activity, was further evaluated for its prevention of stress\u2010 and drug\u2010induced reinstatement of extinguished cocaine conditioned place preference (CPP).<\/jats:p><\/jats:sec><jats:sec><jats:title>KEY RESULTS<\/jats:title><jats:p>The two isomers showed similar affinity and selectivity for \u03ba receptors (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u200330\u201335\u2003nM) as well as \u03ba receptor antagonism<jats:italic>in vitro.<\/jats:italic>As expected, the D\u2010Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose\u2010dependent \u03ba\u2010receptor selective antagonism lasting less than 18\u2003h<jats:italic>in vivo.<\/jats:italic>Pretreatment with this peptide prevented stress\u2010, but not cocaine\u2010induced, reinstatement of extinguished cocaine CPP. In contrast, the L\u2010Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist\/antagonist activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS AND IMPLICATIONS<\/jats:title><jats:p>The L\u2010Trp and the D\u2010Trp isomers of CJ\u201015,208 demonstrate stereospecific opioid activity<jats:italic>in vivo<\/jats:italic>. The relatively brief \u03ba opioid receptor antagonism, coupled with the prevention of stress\u2010induced reinstatement of extinguished cocaine\u2010seeking behaviour, suggests the D\u2010Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1476-5381.2011.01544.x","type":"journal-article","created":{"date-parts":[[2011,6,15]],"date-time":"2011-06-15T07:17:16Z","timestamp":1308122236000},"page":"1097-1108","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Novel opioid cyclic tetrapeptides: Trp isomers of CJ\u201015,208 exhibit distinct opioid receptor agonism and short\u2010acting \u03ba opioid receptor antagonism"],"prefix":"10.1111","volume":"165","author":[{"given":"Nicolette C","family":"Ross","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate J","family":"Reilley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas F","family":"Murray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane V","family":"Aldrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay P","family":"McLaughlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,1,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9105-4"},{"key":"e_1_2_8_3_1","unstructured":"AldrichJV PatkarKA ChappaAK FangW AudusKL LunteSMet\u2003al. 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