Modulation of Renal Excretory Function by the Conformationally Restricted Enantiomeric κ‐Opioid Receptor Agonists: (+) U‐50,488 and (−) U‐50,488

Abstract

Currently, more than half of the drugs in clinical use are chiral compounds. In many instances the enantiomers of chiral drugs demonstrate pronounced differences in biological activity, toxicology, pharmacokinetics, and metabolism. Administration of racemic U‐50,488, a highly selective chiral κ‐opioid receptor agonist, produces a marked sodium and potassium sparing diuresis (i.e. aquaresis), dysphoria, and analgesia in conscious rats. Though U‐50,488 enantiomers have been the subject of various behavioral and analgesic studies, there is a distinct lack of data pertaining to isomers and kappa induced aquaresis. Therefore, the aim of the present study was to pharmacologically characterize the renal excretory effects produced by the isolated (−)‐(1S,2S)‐U‐50,488 versus (+)‐(1R,2R)‐U50,488 enantiomers. Methods Male Sprague‐Dawley rats with an indwelling intracerebroventricular (ICV) cannula were surgically implanted with an arterial, venous, and bladder catheter and continuously infused intravenously (i.v.) with iso‐saline. After stabilization, mean arterial pressure (MAP), heart rate (HR), and urine flow rate (V) were measured in conscious rats for 20‐min before (control) and 90‐min after (experimental) ICV bolus injection (1 ug) of (−)‐(1S,2S)‐U‐50,488, (+)‐(1R,2R)‐U50,488, racemic (+/−)‐U‐50,488, or vehicle (n=6/group). Urine samples were analyzed for urinary sodium excretion (UNaV) and urinary potassium excretion (UKV). Results ICV injection of racemic U‐50,488 (1 ug) produced a significant diuretic (control (C), 56±6, 30‐min, 152±7 ul/min), antinatriuretic (C, 8.7±2.2, 30 min, 3.7±2 ueq/min), and antikaluretic (C, 1.1±0.5; 0.4±0.4 ueq/min) response. At the same dose, both the (−)‐(1S,2S)‐U‐50,488 and (+)‐(1R,2R)‐U50,488 isomers produced a significant sodium and potassium sparing diuresis without changing MAP or HR. At 1 ug, (−)‐(1S,2S)‐U‐50,488 significantly increased peak urine flow rate (C, 58±6 ul/min; 20 min 196±29 ul/min) and decreased urinary sodium (C, 8.9±2.3 μeq/min; 30 min 3.9±0.8 μeq/min) and potassium (C, 0.8±0.2 μeq/min, 30 min, 0.2±0.1 μeq/min) excretion. In contrast, 1 ug of (+)‐(1R,2R)‐U50,488 increased urine flow rate to a lessor magnitude (C, 57±6 ul/min; 10 min 119±26 ul/min) while decreasing urinary sodium excretion (C, 8.0±0.7 μeq/min, 30 min 4.3±1.5 μeq/min) but not urinary potassium excretion. ICV pretreatment (1ug, 10 min) with the kappa antagonist nor‐BNI abolished the kappa‐mediated diuresis by both enantiomers and racemic U‐50,488.ConclusionsThese results indicate (−)‐(1S,2S)‐U‐50,488 is the predominant isomer responsible for producing the centrally mediated aquaresis observed with racemic U‐50,488. Blockade of the aquaresis by ICV nor‐BNI indicates that both enantiomers mediate their renal excretory effects through activation of central kappa receptors. Further renal excretory studies are needed to fully elucidate the pharmacological variances between these two compounds and determine whether a selective entaniomer of U‐50,488 may be used therapeutically as a water diuretic.Support or Funding InformationNIH P30GM106392 (DRK)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.