Among all the compounds the novel L

Among all the compounds, the novel L-748,337 derivative (23d) showed the potent human β3-AR antagonist activity and high lipolysis inhibitory activity in vitro. The vx 765 23d displayed 23-fold more potent β3-AR antagonist activity (EC50 = 0.5117 nM) than that of L-748,337 (EC50 = 11.91 nM) and high selectivity over β2-AR (100-fold) and β1-AR (6-fold). In vivo, compound 23d could alleviate weight loss and inhibit tumor growth in C26 tumor cachexia animal model. In conclusion, in this study, we investigated potent and selective human β3-AR antagonist and demonstrated 23d as a useful in vitro and in vivo pharmacological tool for decreasing the severity of cancer cachexia and inhibiting the growth of cancer cells.
Experimental sections
Introduction Many adults with heart failure (HF) experience significant physical symptoms like dyspnea and fatigue that impair quality-of-life and drive healthcare utilization. The biological underpinnings of symptoms in HF using common objective markers of heart function are unclear,4, 5 however, and mismatches between what patients experience symptomatically and how they present hemodynamically are common. Novel markers related to pathophysiologic mechanisms, such as sympathetic overactivation, may be helpful in understanding the origin and propagation of physical symptoms in HF. Chronic overactivation of the sympathetic nervous system is a well-known phenomenon in HF. More specifically, β-adrenergic receptors are essential molecules in the control of cardiac function and neurohormonal activation in HF. β-adrenergic receptor function is controlled by several molecular mechanisms, one of them being β-adrenergic receptor kinase-1 (βARK1; a.k.a. G protein-coupled receptor kinase-2). With chronic catecholamine stimulation, βARK1 desensitizes and causes internalization of β-adrenergic receptors. Decreased β-adrenergic receptor signaling reduces energy expenditure but also limits the capacity to acutely increase cardiac output. In HF, βARK1 is elevated in myocardial cells and lymphocytes and is detectable in plasma. Hence, the purpose of this study was to quantify the relationship between plasma βARK1 and physical symptoms among adults with HF.
Methods
Results The young, mostly male, and mostly Non-Hispanic Caucasian sample had primarily NYHA Class III or IV HF and non-ischemic etiology (Table 1). The median time since HF diagnosis was approximately 6 years. On average, participants had high filling pressures and low ejection fraction, and the majority were treated with evidence-based therapies. Plasma βARK1 ranged from 0.34 to 126.9 pg/mL. The combination of plasma βARK1 and clinical characteristics significantly explained 25.0% of the variance in HFSPS scores (F(7, 70) = 3.34, p = 0.004) (Table 2). In addition to other clinical characteristics retained in the final model, βARK1 was independently and significantly associated with HFSPS scores (β = 0.22 ± 0.10, p = 0.038). Substituting the log-transformed value of βARK1 demonstrated similar significant results (data not shown). In moderation analysis, plasma βARK1 (β = 1.42 ± 0.31, p < 0.001) and SHFM scores (β = 12.40 ± 1.58, p < 0.001) were independently associated with HFSPS scores. There also was a significant interaction effect of plasma βARK1 and SHFM scores in predicting HFSPS scores (Fig. 1; interaction effect: β = -0.42 ± 0.09, p < 0.001; model: F(5,86) = 49.26, p < 0.001), indicating that the combination of plasma βARK1 and SHFM scores is better at explaining the gradient of HFSPS scores as opposed to either measure alone. Indeed, the spectrum of HFSPS scores more closely followed the range of plasma βARK1 levels compared with the range of SHFM scores. As an example, patients with the worst physical symptoms had higher levels of plasma βARK1 but not higher SHFM scores.