The xamoterol experience in the treatment of heart failure

Quantification of Ligand Bias for Clinically Relevant β2-Adrenergic Receptor Ligands: Implications for Drug Taxonomy

“…Initially, 17 b-adrenergic ligands currently used in various clinical indications (Castle et al, 1993;Cruickshank, 1993;Eichhorn and Young, 2001;Javed and Deedwania, 2009;Ram, 2010) and 2 endogenous ligands were selected to assess their functional selectivity toward 4 signaling pathways: cAMP production, calcium mobilization, ERK1/2 activation, and receptor endocytosis (Tables 1 and 2). For reference purposes, the compounds, structures, binding affinities (from published radioligand binding studies), relative efficacies (previously reported for cAMP production), receptor subtype selectivity profile, and clinical uses are 1 Because model parameter redundancy, it is usually not possible to estimate separate t or K A values for full agonists from direct fitting of the operational model to a full agonist concentration-response curve unless additional experimental manipulations are performed to provide information about other model parameters (e.g., receptor alkylation studies to reduce system maximum responsiveness and thus allow estimation of E m ) or parameter values are constrained to prior known values.…”

“…Hypertension, glaucoma, IHD, migraine, post-MI (Helfand et al, 2007;Baker et al, 2011) Xamoterol 5.55-6.07 (Isogaya et al, 1999;Del Carmine et al, 2002;Baker, 2005 Myocardial ischemia, mild-moderate heart failure (Cruickshank, 1993) IHD, ischemic heart disease; MI, myocardial infarction; NR, no response; NT, not tested.…”

“…As such, we investigated 19 clinically relevant compounds that are used for treating diseases such as asthma, chronic obstructive pulmonary disease, cardiovascular disease, migraine, and glaucoma and determined their signaling efficacy toward four functional outcomes, namely, the cAMP, ERK1/2, and calcium signaling pathways, as well as b 2 AR endocytosis. Importantly, both formal clinical studies and anecdotal observations suggest that some of these compounds may be more efficacious and/or safer than others for certain clinical indications, despite having the same relative efficacy toward the cAMP pathway (Castle et al, 1993;Cruickshank, 1993;Eichhorn and Young, 2001;Javed and Deedwania, 2009;Ram, 2010). Although these differences may be attributed to other properties of the drugs (polypharmacology, pharmacokinetics, etc.…”

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

“…Xamoterol, an agent with partial agonist activity, improved clinical status, exercise capacity, and overall quality of life but significantly increased mortality in patients with congestive heart failure. 30 Bucindolol also had significant beneficial effects on quality of life [31][32][33][34][35][36] but failed to improve mortality in a long-term trial. 12 The reasons for the failure of the BEST trial are not clear, but several explanations have been considered, including the possibility that ␤-adrenergic blockade is not beneficial for all subsets of patients.…”

“…These agents, like others acting downstream in the same pathway (eg, forskolin, phosphodiesterase III inhibitors), have short-term positive effects on hemodynamics and quality of life. 30 None have reduced mortality, however, and most have worsened survival in heart failure. 38 Stimulation of ␤ARs raises intracellular cAMP and predisposes the myocyte to calcium overloading by both cAMP-dependent and -independent means.…”