In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor.

摘要: Abstract [(pF)Phe 4 Aib 7 Arg 14 Lys 15 ]N/OFQ-NH 2 (UFP-112) has been designed as a novel ligand for the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) by combining into same different chemical modifications reported to increase N/OFQ potency. In vitro data obtained in electrically stimulated mouse vas deferens demonstrated that UFP-112 behaved high potency (pEC 50 9.43) full agonist at NOP receptor. effects were sensitive antagonist UFP-101 but not naloxone and no longer evident tissues taken from −/− mice. half life of plasma brain homogenate was 2.6- 3.5-fold higher than N/OFQ. vivo, tail withdrawal assay, (1–100 pmol, i.c.v.) mimicked actions producing pronociceptive after i.c.v. administration antinociceptive when given i.t.; both cases, approximately 100-fold more potent natural produced lasting effects. also hyperphagic effect bell shaped dose response curve with maximum reached 10 pmol. The absent Equi-effective doses (0.1 nmol) (10 nmol) injected mice spontaneous locomotor activity recorded 16 h. clear inhibitory which lasted 60 min while elicited (>6 h). conscious rats, (0.1 10 nmol/kg, i.v.) marked sustained decrease heart rate, blood pressure, urinary sodium excretion profound urine flow. Collectively, these findings demonstrate behaves vivo highly selective able produce long activation receptors.