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
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
References
Clenbuterol, a beta-adrenoceptor agonist, increases relative muscle strength in orthopaedic patients
Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors.
Society of Toxicologic Pathology position paper: organ weight recommendations for toxicology studies
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