Comparison of beta-ligands used in cattle production: structures, safety, and biological effects

Technologies that increase the efficiency and sustainability of food animal production to provide meat for a growing population are necessary and must be used in a manner consistent with good veterinary practices, approved labeled use, and environmental stewardship. Compounds that bind to beta-adrenergic receptors (β-AR), termed beta-adrenergic receptor ligands (β-ligands), are one such technology and have been in use globally for many years. Though all β-ligands share some similarities in structure and function, the significance of their structural and pharmacological differences is sometimes overlooked. Structural variations in these molecules can affect absorption, distribution, metabolism, and excretion as well as cause substantial differences in biological and metabolic effects. Several β-ligands are available for use specifically in cattle production. Ractopamine and zilpaterol are beta-adrenergic agonists approved to increase weight gain, feed efficiency, and carcass leanness in cattle. They both bind to and activate β1- and β2-AR. Lubabegron is a newly developed selective beta-adrenergic modulator with unique structural and functional features. Lubabegron displays antagonistic behavior at the β1- and β2-AR but agonistic behavior at the β3-AR. Lubabegron is approved for use in cattle to reduce ammonia emissions per unit of live or carcass weight. Additionally, lubabegron can withstand prolonged use as the β3-AR lacks structural features needed for desensitization. Due to these unique features of lubabegron, this new β-ligand provides an additional option in cattle production. The individual properties of each β-ligand should be considered when making risk management decisions, as unique properties result in varying human food safety profiles that can determine appropriate safe β-ligand use.

Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response

Signaling diversity of G protein-coupled (GPCR) ligands provides novel opportunities to develop more effective, better-tolerated therapeutics. Taking advantage of these opportunities requires identifying which effectors should be specifically activated or avoided so as to promote desired clinical responses and avoid side effects. However, identifying signaling profiles that support desired clinical outcomes remains challenging. This study describes signaling diversity of mu opioid receptor (MOR) ligands in terms of logistic and operational parameters for ten different in vitro readouts. It then uses unsupervised clustering of curve parameters to: classify MOR ligands according to similarities in type and magnitude of response, associate resulting ligand categories with frequency of undesired events reported to the pharmacovigilance program of the Food and Drug Administration and associate signals to side effects. The ability of the classification method to associate specific in vitro signaling profiles to clinically relevant responses was corroborated using β2-adrenergic receptor ligands.