line of treatment for primary hypertension. Mechanism of action β3-AR are coupled with G proteins, both Gs protein and Gi protein. Gs protein coupled with β3-AR lead to increased activity of the enzyme adenylyl cyclase. Increased activity of adenylyl cyclase leads to increased formation of cyclic adenosine monophosphate (cAMP). β3-AR can also couple with Gi proteins. When they are coupled they lead to decrease in intracellular cAMP. The mechanism of β3-AR and Gi protein has been proposed as a mechanism of action in the heart. When β3-AR are coupled with Gi protein they can act as a brake on β1- and β2 adrenergic receptors to prevent over-activation by opposing the classical inotropic effect of β1 and β2 adrenergic receptors. The smooth muscle cells in the urinary bladder express β3-AR. They have effect on the detrusor muscle which relaxes when the β3-AR are activated. The relaxed detrusor muscle improves filling capacity of the bladder and eases the urge to pass urine. Nitric oxide Another mechanism by which β3-AR agonists exert their relaxative effects on vasculature is by promoting endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. This is believed to be the mechanism by which nebivolol, a selective β1-AR agonist with additional β3-AR agonist activity, exerts its cardio-protective effects. Structure Activity Relationships (SAR) Basic structure of β3-adrenergic receptor agonists β3-AR agonists have the basic structure 2-amino-1-phenylethan-1-ol but have variations that affect the selectivity of the agonist. Binding to the β3-adrenergic receptor Visual inspection of selective β3-AR agonists revealed that they bind deep in the binding pocket of the receptors and exhibit some H-bonds and or hydrophobic interactions with the receptor. Activity of β3-adrenergic receptor agonists 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