title: Dmt-Tic-NH-CH2-Bid (UFP-502), a potent DOP receptor agonist: in vitro and in vivo studies.
abstract: Knockout and pharmacological studies demonstrated that the activation of delta opioid peptide (DOP) receptors produces antidepressant-like effects in rodents. Here we report the results obtained with the novel DOP ligand H-Dmt-Tic-NH-CH(2)-Bid (UFP-502). UFP-502 bound with high affinity (pK(i) 9.43) to recombinant DOP receptors displaying moderate selectivity over MOP and KOP. In CHO(hDOP) [(35)S]GTPgammaS binding and mouse vas deferens experiments, UFP-502 behaved as a potent (pEC(50) 10.09 and 10.70, respectively) full agonist. In these preparations, naloxone, naltrindole and N,N(CH(3))(2)Dmt-Tic-OH showed similar pA(2) values against UFP-502 and DPDPE and the same rank order of potency. In vivo in mice, UFP-502 mimicked DPDPE actions, producing a significant reduction of immobility time after intracerebroventricular administration in the forced swimming test and a clear antinociceptive effect after intrathecal injection in the tail withdrawal assay. However, while the effects of DPDPE were fully prevented by naltrindole those evoked by UFP-502 were unaffected (tail withdrawal assay) or only partially reversed (forced swimming test). In conclusion, UFP-502 represents a novel and useful chemical template for the design of selective agonists for the DOP receptor.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, and Neuroscience Centre, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Vergura
authors.forename: Elena
authors.initials: E
authors.lastname: Valenti
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hebbes
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Gavioli
authors.forename: Barbara
authors.initials: B
authors.lastname: Spagnolo
authors.forename: John
authors.initials: J
authors.lastname: McDonald
authors.forename: David G
authors.initials: DG
authors.lastname: Lambert
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics
chemical_list: C507403:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1H-benzimidazol-2-ylmethylamide; D001562:Benzimidazoles; D004151:Dipeptides; D017465:Receptors, Opioid, delta