{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:12:59Z","timestamp":1788315179002,"version":"build-2803163510"},"reference-count":20,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2015,3,17]],"date-time":"2015-03-17T00:00:00Z","timestamp":1426550400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a,b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a,b, we synthesized analogues of 2a,b that lacked the 4-methyl (5a,b), 3-methyl (6a,b), and both the 3- and 4-methyl group (7a,b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were nonselective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts, and (3) compounds 2a,b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogues 5a,b, 6a,b, and 7a,b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a,b) gives (4a,b), which are opioid antagonists.<\/jats:p>","DOI":"10.1021\/jm500184j","type":"journal-article","created":{"date-parts":[[2014,3,17]],"date-time":"2014-03-17T15:00:51Z","timestamp":1395068451000},"page":"3140-3147","source":"Crossref","is-referenced-by-count":7,"title":["Effect of the 3- and 4-Methyl\nGroups on the\nOpioid Receptor Properties of N-Substituted\n                    <i>trans<\/i>\n                    -3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines"],"prefix":"10.1021","volume":"57","author":[{"given":"Chad M.","family":"Kormos","sequence":"first","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Cueva","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moses G.","family":"Gichinga","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott P.","family":"Runyon","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence E.","family":"Brieaddy","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Wayne","family":"Mascarella","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian P.","family":"Gilmour","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herna\u0301n A.","family":"Navarro","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Ivy","family":"Carroll","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , , P.O. Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,3,17]]},"reference":[{"key":"2026090121144082100_cit1","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/0471266949.bmc251","article-title":"Opioid Receptor\nLigands","volume-title":"Burger\u2019s Medicinal Chemistry,\nDrug Discovery and Development","author":"McCurdy","year":"2010","edition":"7"},{"key":"2026090121144082100_cit2","first-page":"197","article-title":"Novel Developments\nof N-Methylbenzomorphan Narcotic Antagonists","volume-title":"Characteristics and Function of Opioids","author":"Michne","year":"1978"},{"key":"2026090121144082100_cit3","first-page":"33","article-title":"Naloxone, Naltrexone\nand Related Noroxymorphones","volume-title":"Narcotic Antagonists,\nAdvances in Biochemical Psychopharmacology","author":"Blumberg","year":"1973"},{"key":"2026090121144082100_cit4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/B978-0-08-010895-7.50003-0","volume-title":"Synthetic\nAnalgesics, Part IIa, Morphinans","author":"Hellerbach","year":"1966"},{"key":"2026090121144082100_cit5","first-page":"115","volume-title":"Synthetic Analgesics,\nPart IIb, 6,7-Benzomorphans","author":"Eddy","year":"1966"},{"key":"2026090121144082100_cit6","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1021\/jm00398a011","article-title":"Synthesis\nand analgesic properties\nof N-substituted trans-4a-aryldecahydroisoquinolines","volume":"31","author":"Zimmerman","year":"1988","journal-title":"J. Med. Chem."},{"key":"2026090121144082100_cit7","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/275332a0","article-title":"New structural concepts\nfor narcotic antagonists defined in a 4-phenylpiperidine series","volume":"275","author":"Zimmerman","year":"1978","journal-title":"Nature"},{"key":"2026090121144082100_cit8","first-page":"237","article-title":"Further Investigation\nof Novel 3-Methyl-4-phenylpiperidine Narcotic Antagonists","volume-title":"Proceedings of the 40th Annual Scientific Meeting of\nthe Committee on Problems of Drug Dependence","author":"Zimmerman","year":"1978"},{"key":"2026090121144082100_cit9","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1021\/jm00072a001","article-title":"Structure\u2013activity\nrelationships of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine\nantagonists for \u03bc and \u03ba opioid receptors","volume":"36","author":"Zimmerman","year":"1993","journal-title":"J. Med. Chem."},{"key":"2026090121144082100_cit10","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1021\/jm980063g","article-title":"Investigation of the N-substituent conformation governing\npotency and mu receptor subtype-selectivity in (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine\nopioid antagonists","volume":"41","author":"Thomas","year":"1998","journal-title":"J. Med. Chem."},{"key":"2026090121144082100_cit11","doi-asserted-by":"crossref","first-page":"5188","DOI":"10.1021\/jm980511k","article-title":"Identification of\nan opioid \u03ba receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine","volume":"41","author":"Thomas","year":"1998","journal-title":"J. Med. Chem."},{"key":"2026090121144082100_cit12","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1021\/jm015521r","article-title":"Identification of\nthe first trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess\nhighly potent and selective opioid kappa receptor antagonist activity","volume":"44","author":"Thomas","year":"2001","journal-title":"J. Med. Chem."},{"key":"2026090121144082100_cit13","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1021\/jm030094y","article-title":"Identification of (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide\nas a novel potent and selective opioid kappa receptor antagonist","volume":"46","author":"Thomas","year":"2003","journal-title":"J. Med. Chem."},{"key":"2026090121144082100_cit14","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1021\/jm030092d","article-title":"2002 Medicinal\nChemistry Division Award address: monoamine transporters and opioid\nreceptors. Targets for addiction therapy","volume":"46","author":"Carroll","year":"2003","journal-title":"J.\nMed. Chem."},{"key":"2026090121144082100_cit15","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1021\/ml100126b","article-title":"1-Substituted\n4-(3-hydroxyphenyl)piperazines\nare pure opioid receptor antagonists","volume":"1","author":"Carroll","year":"2010","journal-title":"ACS Med.\nChem. Lett."},{"key":"2026090121144082100_cit16","doi-asserted-by":"crossref","first-page":"4795","DOI":"10.1021\/jo00281a019","article-title":"Synthesis of picenadol via metalloenamine\nalkylation methodology","volume":"54","author":"Barnett","year":"1989","journal-title":"J. Org. Chem."},{"key":"2026090121144082100_cit17","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1021\/jm00160a039","article-title":"Investigation\nof 4-(3-hydroxyphenyl)-4-methylpipecolic\nacid as a conformationally restricted mimic of the tyrosyl residue\nof leucine-enkephalinamide","volume":"29","author":"Sugg","year":"1986","journal-title":"J. Med. Chem."},{"key":"2026090121144082100_cit18","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1021\/ja01548a030","article-title":"Piperidine derivatives.\nXXX. 1,4-Dialkyl-4-arylpiperidines","volume":"80","author":"McElvain","year":"1958","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026090121144082100_cit19","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/chir.530010305","article-title":"Stereochemical\ninfluences upon the\nopioid ligand activities of 4-alkyl-4-arylpiperidine derivatives","volume":"1","author":"Casy","year":"1989","journal-title":"Chirality"},{"key":"2026090121144082100_cit20","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.1021\/jm00072a002","article-title":"3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines:\nopioid antagonists with potent anorectant activity","volume":"36","author":"Mitch","year":"1993","journal-title":"J. Med. Chem."}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm500184j","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/7\/3140\/15118806\/jm500184j.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/7\/3140\/15118806\/jm500184j.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:14:52Z","timestamp":1788311692000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/7\/3140\/1435590\/Effect-of-the-3-and-4-Methyl-Groups-on-the-Opioid"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,17]]},"references-count":20,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2014,3,17]]},"published-print":{"date-parts":[[2014,4,10]]}},"URL":"https:\/\/doi.org\/10.1021\/jm500184j","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,17]]}}}