RT Journal Article
SR Electronic
T1 Pharmacological Characterization of a Novel 5-Hydroxybenzothiazolone-Derived <em>β</em><sub>2</sub>-Adrenoceptor Agonist with Functional Selectivity for Anabolic Effects on Skeletal Muscle Resulting in a Wider Cardiovascular Safety Window in Preclinical Studies
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 188
OP 199
DO 10.1124/jpet.118.255307
VO 369
IS 2
A1 Magdalena Koziczak-Holbro
A1 Dean F. Rigel
A1 Bérengère Dumotier
A1 David A. Sykes
A1 Jeffrey Tsao
A1 Ngoc-Hong Nguyen
A1 Julian Bösch
A1 Marie Jourdain
A1 Ludivine Flotte
A1 Yuichiro Adachi
A1 Michael Kiffe
A1 Moïse Azria
A1 Robin A. Fairhurst
A1 Steven J. Charlton
A1 Brian P. Richardson
A1 Estelle Lach-Trifilieff
A1 David J. Glass
A1 Thomas Ullrich
A1 Shinji Hatakeyama
YR 2019
UL http://jpet.aspetjournals.org/content/369/2/188.abstract
AB The anabolic effects of β2-adrenoceptor (β2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of β2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived β2-AR agonist in comparison with formoterol as a representative β2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human β2-AR and selectivity over the β1-AR and β3-AR. 5-HOB also shows potent agonistic activity at the β2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue–derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional β2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects.