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-CH2-Bid (UFP-502). UFP-502 bound with high affinity (pKi 9.43) to recombinant DOP receptors displaying moderate selectivity over MOP and KOP. In CHOhDOP [35S]GTPgS binding and mouse vas deferens experiments, UFP-502 behaved as a potent (pEC50 10.09 and 10.70, respectively) full agonist. In these preparations, naloxone, naltrindole and N,N(CH3)2Dmt-Tic-OH showed similar pA2 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 vivo studies
VERGURA, Raffaella;GAVIOLI, Elaine Cristina;SPAGNOLO, Barbara;SALVADORI, Severo;REGOLI, Domenico;CALO', Girolamo
2006
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-CH2-Bid (UFP-502). UFP-502 bound with high affinity (pKi 9.43) to recombinant DOP receptors displaying moderate selectivity over MOP and KOP. In CHOhDOP [35S]GTPgS binding and mouse vas deferens experiments, UFP-502 behaved as a potent (pEC50 10.09 and 10.70, respectively) full agonist. In these preparations, naloxone, naltrindole and N,N(CH3)2Dmt-Tic-OH showed similar pA2 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.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
