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

Abstract

The opioid-like peptide nociceptin/orphanin FQ (N/OFQ) produces marked cardiovascular and renal responses after central or peripheral administration in rats. Due to their ability to behave as full/partial agonists or antagonists in different cellular and tissue assays, the present studies were performed to determine how compounds classified as N/OFQ peptide (NOP) receptor partial agonists ([F/G]N/OFQ(1-13)-NH 2 , Ac-RYYRIK-NH 2 , and Ac-RYYRWK-NH 2 ) affect cardiovascular and renal function in vivo. In conscious Sprague-Dawley rats, intracerebroventricular (i.c.v.) administration of each of the three NOP receptor ligands produced profound cardiovascular (depressor), renal excretory (water diuresis), and renal sympathetic nerve activity (inhibitory) responses that were similar to those produced by i.c.v. injection of the native ligand N/OFQ. In contrast, in other groups of rats, the intravenous (i.v.) bolus injection of these same NOP receptor ligands produced responses unlike N/OFQ; N/OFQ evoked an immediate and profound bradycardia and hypotension with no change in urine output, whereas all purported NOP receptor partial agonists elicited a subtle slow onset hypotension, no change in heart rate, and a marked water diuresis. In other studies, i.v. bolus pretreatment of rats with NOP receptor partial agonists prevented/attenuated the cardiovascular depressor effects pro-

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

“…Ac-RYYRWK-NH 2 was chosen as the parent compound based on the results of investigations in which we demonstrated that the NOP receptor partial agonist Ac-RYYRWK-NH 2 produced a modest water diuresis after i.v. bolus injection in conscious rats (Kapusta et al, 2005). In addition to this compound's agonist-like effects on kidney function, we also showed that Ac-RYYRWK-NH 2 (and other ligands historically classified as NOP receptor partial agonists; Calo' et al, 2000) behaved as a weak partial agonist, eliciting a slight reduction in mean arterial pressure without affecting heart rate.…”

“…However, the enzymatic instability of endogenous N/OFQ makes this peptide unsuitable for clinical use. To circumvent this problem, we developed a novel NOP receptor ligand that was created by applying the structure-inducing probe (SIP) technology (Larsen and Holm, 1998;Larsen, 1999;Larsen et al, 2001;Kapusta et al, 2002) to the compound Ac-RYYRWK-NH 2 , a purported NOP receptor partial agonist (Dooley et al, 1997;Kapusta et al, 2005). The principle of the SIP technology is that a short (5-10-amino acid) sequence of certain charged amino acids (e.g., lysine or asparagine) forms an ␣-helical structure, which when attached to the C or N terminus of another peptide may twist the whole peptide into an ␣-helix and prevent enzymatic degradation (Larsen et al, 2001;Larsen, 2003).…”

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

“…In addition to increased potency, UFP-112 also produced markedly longer cardiovascular responses than N/OFQ. In this regard, the changes in mean arterial pressure and heart rate produced by N/OFQ at 10 nmol/kg (present study; figures 7 and 8) or higher (30 and 100 nmol/kg; [33]) recovered within 10-min post-drug injection. At the 10 nmol/ kg dose UFP-112 significantly decreased heart rate and mean arterial pressure throughout the 80-min protocol (figure 8).…”

“…These responses to UFP-112 are different to those to the natural ligand N/OFQ, which at all previously tested doses up to 1000 nmol/kg i.v. bolus has not produced diuresis ( [33] and Kapusta et al, unpublished results). There are two possible explanations for the ability of UFP-112 to produce a diuretic response after bolus injection i.v.…”

“…the UFP-112-induced increase in urine flow rate was delayed in onset (approximately 30-min), of relatively long duration (50-60 min), and associated with a reduction in urinary sodium excretion (not statistically significant). Of note, when administered at 10 nmol/kg N/OFQ did not alter urine flow rate (figure 8), and instead at higher doses (30, 100, 300, 1000 nmol/kg, i.v) produced antidiuresis ( [33] and Kapusta personal observations). Finally, it should be noted that following i.v.…”