Pharmacological Characterization of a Novel 5-Hydroxybenzothiazolone-Derived β2 -Adrenoceptor Agonist with Functional Selectivity for Anabolic Effects on Skeletal Muscle Resulting in a Wider Cardiovascular Safety Window in Preclinical Studies

The Journal of Pharmacology and Experimental Therapeutics
Magdalena Koziczak-HolbroShinji Hatakeyama

Abstract

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...Continue Reading

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Citations

Jul 21, 2020·American Journal of Physiology. Renal Physiology·Jun YangMargot S Damaser
Jul 8, 2020·International Journal of Molecular Sciences·Mattia ScalabrinT Scott Bowen
Jan 22, 2020·Drug Testing and Analysis·Morten HostrupAnders Krogh Lemminger
Feb 12, 2021·Scientific Reports·Naoki KuramotoWataru Ogawa
Jun 26, 2021·The AAPS Journal·Ernest L VallorzHeidi M Mansour
Jul 29, 2021·Advanced Science·Sevgican DemirBilgen Ekim Üstünel
Oct 23, 2021·The Journal of Physiology·Morten Hostrup, Johan Onslev

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