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. History of development In 1984 the β3 receptor was described as the third group of beta receptors in adipose tissue. This led to the development of agonist targeted at obesity and diabetes. In 1999 the function of the β3 in detrusor muscles was defined which opened the way for development of β3-AR agonist for OAB. In 2001 Mirabegron began clinical development in phase 1 clinical study. The indications were type 2 diabetes, lower urinary tract symptoms, OAB and bladder outlet obstruction. From 2004 to 2008 phase 2 clinical trials were performed. However the development of Mirabegron for type two diabetes was interrupted. In 2007 GlaxoSmithKline entered phase 1 clinical trials with Solabegron with the indication for OAB as well as a trial with the indication for Irritable bowel syndrome (IBS). From 2009 to 2011 Astellas Pharma concluded phase 3 clinical trials for the treatment of OAB with mirabegron. In July 2012 mirabegron was the first β3-AR agonist to be approved by the FDA and in October