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

Abstract

In conscious rats, intravenous (i.v.) administration of the hexapeptide Ac-RYYRWK-NH 2 , 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-RYYR-WKKKKKKK-NH 2 ), which was created by conjugation of a structure-inducing probe (SIP) (i.e., K 6 sequence) to Ac-RYYRWK-NH 2 . In cells transfected with human NOP receptors, both Ac-RYYRWK-NH 2 and ZP120 displaced [ 3 H]N/OFQ (both peptides, pK i ϭ 9.6), and similar to N/OFQ inhibited forskolininduced cAMP formation (Ac-RYYRWK-NH 2 , pEC 50 ϭ 9.2; ZP120, 9.3; N/OFQ, 9.7). In the mouse vas deferens assay (MVD), Ac-RYYRWK-NH 2 and ZP120 behaved as partial agonists, inhibiting electrically induced contractions with similar pEC 50 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-NH 2 . In vivo, doseresponse 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-NH 2 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.

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

“…Although not tested, UFP-112 may produce diuresis by activating a potential peripheral (e.g. kidney; [26]) diuretic pathway similar to that previously proposed for NOP receptor partial agonists [34]. The ability of UFP-112 (but not N/OFQ) to reach these sites after i.v.…”

“…These pharmacological features are highly desirable especially for investigating those conditions and states in which a selective and prolonged stimulation of NOP receptor is beneficial, including anxiety states [21,28], drug addiction [15,48], anorectic conditions [16], spinal analgesia (as indicated by laboratory animals [54] as well as primate [35] studies), cough and possibly other respiratory diseases [40], acute heart failure [26,34], and, as indicated by clinical studies, urinary incontinence due to overactive bladder [37][38][39]. Peak changes in mean arterial pressure and heart rate produced immediately following i.v.…”

Functional Selectivity of Nociceptin/Orphanin FQ Peptide Receptor Partial Agonists on Cardiovascular and Renal Function

“…Based on the observations by Corbani et al (2004), the initiation/onset of the renal excretory responses to NOP receptor partial agonists may be related to sustained ligand receptor binding/coupling and less potential to induce desensitization than full NOP receptor agonists such as N/OFQ. Instead, the duration of the renal excretory responses may be related to the dose and/or metabolic stability of the NOP receptor ligand (Kapusta et al, 2005). Finally, it remains to be determined whether different NOP receptor partial agonists undergo tissue-specific metabolism similar to N/OFQ (Terenius et al, 2000) and whether potential active fragments affect cardiovascular and renal function by NOP receptor-dependent or -independent pathways.…”

“…Based on their ability to produce a selective water diuresis after i.v. bolus injection without apparent adverse cardiovascular or CNS effects, we propose that metabolically stable NOP receptor partial agonists (e.g., ZP120; Kapusta et al, 2005) may be useful therapeutically as novel peripherally acting aquaretics for the acute management of severe water retention and/or hyponatremia.…”

Differential Down-Regulation of Aquaporin-2 in Rat Kidney Zones by Peripheral Nociceptin/Orphanin FQ Receptor Agonism and Vasopressin Type-2 Receptor Antagonism

“…ZP120 does not cross the blood-brain barrier (Rizzi et al, 2002), bolus injection data suggest that i.v. nociceptin/ZP120 might have central effects on water homeostasis control (Kapusta et al, 1997(Kapusta et al, , 2005. Therefore, we wanted additional data to address a possible AVP plasma concentration-lowering effect by peripheral NOP stimulation.…”