Anxiolytic- and antidepressant-like activities of H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), a novel selective delta opioid receptor agonist.
Knockout and pharmacological studies have shown that delta opioid peptide (DOP) receptor signalling regulates emotional responses. In the present study, the in vitro and in vivo pharmacological profile of the DOP ligand, H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512) was investigated. In receptor binding experiments performed on membranes of CHO cells expressing the human recombinant opioid receptors, UFP-512 displayed very high affinity (pKi 10.20) and selectivity (>150-fold) for DOP sites. In functional studies ([35S]GTP gamma S binding in CHOhDOP membranes and electrically stimulated mouse vas deferens) UFP-512 behaved as a DOP selective full agonist showing potency values more than 100-fold higher than DPDPE. In vivo, in the mouse forced swimming test, UFP-512 reduced immobility time both after intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration. Similar effects were recorded in rats. Moreover, UFP-512 evoked anxiolytic-like effects in the mouse elevated plus maze and light-dark aversion assays. All these in vivo actions of UFP-512 were fully prevented by the selective DOP antagonist naltrindole (3 mg/kg, s.c.). In conclusion, the present findings demonstrate that UFP-512 behaves as a highly potent and selective agonist at DOP receptors and corroborate the proposal that the selective activation of DOP receptors elicits robust anxiolytic- and antidepressant-like effects in rodents.
Vergura
Raffaella
R
Department of Experimental and Clinical Medicine, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy.
Balboni
Gianfranco
G
Spagnolo
Barbara
B
Gavioli
Elaine
E
Lambert
David G
DG
McDonald
John
J
Trapella
Claudio
C
Lazarus
Lawrence H
LH
Regoli
Domenico
D
Guerrini
Remo
R
Salvadori
Severo
S
Caló
Girolamo
G
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003624:Darkness; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008024:Ligands; D008027:Light; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D012153:Retention, Psychology / Q000187:drug effects; D013329:Structure-Activity Relationship; D013550:Swimming / Q000523:psychology
C526539:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1H-benzimidazol-2-yl)(carboxymethyl)methylamide; D000928:Antidepressive Agents; D001562:Benzimidazoles; D008024:Ligands; D009842:Oligopeptides; D017465:Receptors, Opioid, delta