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.
Dmt-Tic-NH-CH2-Bid (UFP-502), a Potent DOP Receptor Agonist; In Vitro and in Vitro Studies
BALBONI, GIANFRANCO;
2006-01-01
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.
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