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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacodynamic Characterization of ZP120 (Ac-RYYRWKKKKKKK-NH₂), a Novel, Functionally Selective Nociceptin/Orphanin FQ Peptide Receptor Partial Agonist with Sodium-Potassium-Sparing Aquaretic Activity

Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (D.R.K., V.A.K.); and Zealand Pharma A/S, Glostrup, Denmark (C.T., E.M., M.M.V., C.Q., J.S.P.)

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, pK_i = 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.

Address correspondence to: Dr. Daniel R. Kapusta, Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112. E-mail: dkapus{at}lsuhsc.edu

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