page_title: Beta3-adrenergic agonist
section_title: Activity of β3-adrenergic receptor agonists
hierarchical_section_title: Beta3-adrenergic agonist / Structure Activity Relationships (SAR) / Activity of β3-adrenergic receptor agonists
caption_attribution_description: English: Beta 3 Adrenergic Receptor Agonist
context_page_description: The β₃ adrenergic receptor agonist or β₃-adrenoceptor agonist, also known as β₃-AR agonist, are a class of medicine that bind selectively to β₃-adrenergic receptors.
  β₃-AR agonists for the treatment of obesity and type 2 diabetes have been in developmental stages within many large pharmaceutical companies since the early 1990s with without successfully delivering an anti-obesity product to the market. More recently pharmaceutical companies have developed selective β₃-AR agonists targeted at urinary inconsistencies and in 2012 Mirabegron was the first β₃-AR agonist to be approved in the United States and Europe for the treatment of overactive bladder syndrome.
context_section_description: The R-group on the following picture determines α- or β-adrenergic receptor selectivity. The larger the R-group is, the greater the β-receptor selectivity.
  The basic structure of  β-AR subtypes exhibit sequence similarity greater than 70% suggesting that the 3-dimensional structure of theses subtypes is similar. While the overall structure sequence is 70% identical the residue sites of the ligand binding pocket have an even higher similarity (75%-85%), making development of highly selective ligands difficult. The β₃-AR unlike other β-adrenergic receptors has a higher affinity to ligands with a pyrimidine or m-chlorobenzyl ring rather than catecholamine like the other beta receptors subtypes.
  Noticeable ligand binding sites are the hydrophobic interaction of the aromatic ring, attached to the β-hydroxyl chiral carbon on the left-hand-side, to hydrophobic microdomains on TM3 and TM6 deep in the binding pocket. Additional hydrophobic side groups attached on this aromatic ring have been shown to increase hydrophobic contact in this region. The central hydroxyl group and the central protonated amine form strong hydrogen bonds with the TM7 and TM3 subunits. The hydrogen bonding of the central protonated amine to Y³³⁶ on the TM7 of the β₃-AR serves as an important binding site for the ligand, aligning it properly for the deeper hydrophobic interaction between LHS aromatic ring and TM3 and TM6. This interaction is consistent between the ligands.
  Most of the selective agonists have an aromatic ring formation or another hydrophobic region, around 2-3 carbons from the central protonated amine group, which interacts with the superficial extracellular (ELC2) domain on the receptor. The stereochemistry of this aromatic group and its interactions with the ECL2 affect the ability of the ligand to align properly in the deep binding pocket and is an important factor for the total affinity of the ligand.
  The addition of a proton donating group (e.g. acid, amide) on the right-hand-side terminus contributes to a strong bifurcated hydrogen bonding to the R³¹⁵ of  TM6. Those ligands that do not have an acidic group have some other form of strong hydrogen bonding group that interacts with R³¹⁵, such as a thiazole. This binding site differs between the different beta receptors subtypes and contributes to the β₃ selectivity.
caption: C
              
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                28
              
              
                
              
            
            
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      {\displaystyle {\ce {C25H28N4O2S}}}
exif: {}