β(3)-Adrenoceptor agonists and (antagonists as) inverse agonists history, perspective, constitutive activity, and...

β(3)-Adrenergic receptor (β(3)-AR) is expressed in several tissues and is considered a drug target for the treatment of several pathologies such as obesity, type 2 diabetes, cachexia, metabolic syndrome, heart failure, anxiety and depressive disorders, preterm labor, overactive bladder, control colon motility, and of coadjuvants in colon cancer therapy. It is a seven-transmembrane domain (7TD) G-protein coupled receptor and is usually coupled to a Gs-protein (Gi-protein in very few cases), and its stimulation increases the production of cAMP. A lot of β(3)-AR agonists have been uncovered and extensively characterized. Conversely, very little is known about β(3)-AR inverse agonists that would suppress the agonist-independent activity (constitutive activity) of the receptor by stabilizing it in its inactive state. This chapter attempts to outline (a) the importance of the β(3)-AR as a therapeutic target through the disquisition of its role in human health (physiology) and disease (pathology); (b) the description of β(3)-AR structure [amino acid sequence and 7TD organization]; (c) the medicinal chemistry of β(3)-AR: 7TD amino acid-ligand specific interactions, β-adrenoreceptor subtype selectivity, stereospecific interactions and biological activity relationships, inverse agonism and blockage of β(3)-adrenoceptor constitutive activity; and (d) β(3)-AR inverse agonists. The detailed procedure to prepare and assess the biological activity/selectivity of the more potent and selective β(3)-AR inverse agonists (SP-1e and SP-1g) up to now known is also described.