title: Assessment of substitution in the second pharmacophore of Dmt-Tic analogues.
abstract: The Dmt-Tic pharmacophore exhibits potent delta-opioid receptor antagonism. Analogues with substitutions in the second pharmacophore with (1, 1') or without a COOH function (2-9) were synthesized: several had high delta affinity (1', 2, 7, and 9), but exhibited low to non-selectivity toward mu receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high delta antagonism (pA2 7.4-7.9) (1', 2, and 9) and modest mu agonism, pEC50 (6.1-6.3) (1', 2, 8, and 9), but with Emax values analogous to dermorphin. These Dmt-Tic analogues with mixed delta antagonist/mu agonist properties would appear to be better candidates as analgesics than pure mu agonists.
authors.affiliation: Medicinal Chemistry and Toxicology, University of Naples, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Santagada
authors.forename: G
authors.initials: G
authors.lastname: Balboni
authors.forename: G
authors.initials: G
authors.lastname: Caliendo
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
authors.forename: C
authors.initials: C
authors.lastname: Bianchi
authors.forename: S D
authors.initials: SD
authors.lastname: Bryant
authors.forename: L H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis / Q000378:metabolism*; D051379:Mice; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*
chemical_list: D000700:Analgesics; D004151:Dipeptides; D007546:Isoquinolines; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C076121:2',6'-dimethyltyrosine; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid; D014443:Tyrosine