Abstract
In conscious rats, intravenous (i.v.) administration of the hexapeptide Ac-RYYRWK-NH2, a partial agonist of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor, produces a selective water diuresis without marked cardiovascular or behavioral effects. The present study examined the in vitro and in vivo pharmacodynamic profile of the novel and potentially metabolically stable NOP receptor ligand ZP120 (Ac-RYYRWKKKKKKK-NH2), which was created by conjugation of a structure-inducing probe (SIP) (i.e., K6 sequence) to Ac-RYYRWK-NH2. In cells transfected with human NOP receptors, both Ac-RYYRWK-NH2 and ZP120 displaced [3H]N/OFQ (both peptides, pKi = 9.6), and similar to N/OFQ inhibited forskolin-induced cAMP formation (Ac-RYYRWK-NH2, pEC50 = 9.2; ZP120, 9.3; N/OFQ, 9.7). In the mouse vas deferens assay (MVD), Ac-RYYRWK-NH2 and ZP120 behaved as partial agonists, inhibiting electrically induced contractions with similar pEC50 values (9.0 and 8.6, respectively) but with submaximal efficacy compared with N/OFQ. In MVD, both peptides blocked the responses to N/OFQ, with ZP120 being approximately 50-fold more potent than Ac-RYYRWK-NH2. In vivo, dose-response studies in rats showed that at doses (i.v. bolus or i.v. infusion) that produced a sodium-potassium-sparing aquaresis, ZP120 and Ac-RYYRWK-NH2 elicited a mild vasodilatory response without reflex tachycardia. However, the renal responses to ZP120 were of greater magnitude and duration. Finally, each peptide blocked the bradycardia and hypotension to N/OFQ in conscious rats, but the effect of ZP120 was of much greater duration. Together, these findings demonstrate that ZP120 is a novel, functionally selective SIP-modified NOP receptor partial agonist with increased biological activity and sodium-potassium-sparing aquaretic activity, the actions of which may be useful in the management of hyponatremia/hypokalemia in water-retaining states.
Footnotes
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This work was supported by funds provided by Zealand Pharma A/S; National Institutes of Health Grants DK43337, DK02605, and HL71212; and American Heart Association, Southeastern Affiliate Grant 0255314B (to D.R.K.). We note that funds made available to D.R.K. from the American Heart Association Grant 0255314B were entirely provided to the American Heart Association by a gracious donation from Herbert H. McElveen (DeRidder, LA).
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doi:10.1124/jpet.105.083436.
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ABBREVIATIONS: N/OFQ, nociceptin/orphanin FQ; NOP, nociceptin/orphanin FQ peptide; CNS, central nervous system; SIP, structure-inducing probe; ZP120, Ac-RYYRWKKKKKKK-NH2; hNOP, human nociceptin/orphanin FQ peptide receptor; MVD, mouse vas deferens; HEK, human embryonic kidney; ANOVA, analysis of variance; CompB, 1-[(±)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; Ro64-6198, (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
- Received January 10, 2005.
- Accepted April 18, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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