title: Properties of TAN-67, a nonpeptidic delta-opioid receptor agonist, at cloned human delta- and mu-opioid receptors.
abstract: 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydro-quinolino[2,3,30g]isoquinoline (TAN-67) is a nonpeptidic delta-opioid receptor agonist. This report describes its receptor binding affinity and agonist potency at human and mouse delta and mu-opioid receptors. The binding affinities of TAN-67 and the cyclic enkephalin analog, (D-Pen2, 4'-Cl-Phe4, D-Pen5]enkephalin (pCl-DPDPE) were measured by radioligand binding inhibition studies at mouse and human variants of the delta and mu-opioid receptor using [3H]Naltrindole and [3H]D-Phe-Cys-Tyr-D-Trp-Orn-Thr -Pen-Thr-NH2, respectively. TAN-67 showed high binding affinity (Ki = 0.647 nM) at the human delta-opioid receptor and high delta-opioid receptor binding selectivity ( > 1000-fold) relative to the human mu-opioid receptor. TAN-67 also showed high potency (EC50 = 1.72 nM) for the inhibition of forskolin-stimulated cAMP accumulation at human delta-opioid receptors expressed by intact Chinese hamster ovary cells but low potency (EC50 = 1520 nM) at human mu-opioid receptors expressed by intact B82 mouse fibroblast cells. The results show that TAN-67 has similar binding affinities, selectivity and potencies as pCl-DPDPE at human delta and mu-opioid receptors. These results combined with the nonpeptidic structure of TAN-67 suggest that this compound has therapeutic potential as a delta-opioid receptor agonist.
authors.affiliation: University of Arizona College of Medicine Department of Pharmacology, Tucson 85724, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Knapp
authors.forename: R
authors.initials: R
authors.lastname: Landsman
authors.forename: S
authors.initials: S
authors.lastname: Waite
authors.forename: E
authors.initials: E
authors.lastname: Malatynska
authors.forename: E
authors.initials: E
authors.lastname: Varga
authors.forename: W
authors.initials: W
authors.lastname: Haq
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: W R
authors.initials: WR
authors.lastname: Roeske
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.forename: H I
authors.initials: HI
authors.lastname: Yamamura
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D011804:Quinolines / Q000494:pharmacology*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*
chemical_list: D000700:Analgesics; D011804:Quinolines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C094142:TAN 67; D005576:Colforsin; D000242:Cyclic AMP