Design of Oxytocin Analogs.

The neurohypophyseal hormone oxytocin (OT) and related modulators of the oxytocin receptor (OTR) have been the subject of intensive research for nearly seven decades. Despite having rather poor drug-like properties, OT is used as a treatment for labor induction, postpartum hemorrhage, and lactation support. The potential use of OT in the treatment of central nervous system (CNS)-related diseases has recently renewed interest in the pharmacology of OT. Oxytocin is one of the most extensively studied cyclic peptides and since the elucidation of its structure in 1953 thousands of peptidic OT analogs with antagonistic and agonistic properties have been synthesized and biologically evaluated. Among them are atosiban, a mixed oxytocin receptor (OTR)/vasopressin 1a receptor (V1aR) antagonist used as a tocolytic agent approved (in certain countries), and carbetocin, a longer acting OTR agonist on the market for the treatment of postpartum hemorrhage. Many other OT analogs with improved pharmacological properties (e.g., barusiban, Antag III) have been identified. These peptides have been tested in clinical trials and/or used as pharmacological tools. In this chapter, the modifications of the OT molecule that led to the discovery of these compounds are reviewed.