**Abstract**

The functions of the pineal hormone melatonin are of intense and continuous interest. Synthetic melatonin receptor analogues, as agonists and antagonists, have been explored, and the molecule can be viewed as consisting of an indole nucleus, acting mainly as a spacer, and the C5-OMe and the C3-ethylamido side chains, acting as pharmacophoric components. The present chapter focuses on the synthetic routes towards these melatonin derivatives, first the aromatic nucleus, then the functionalities that have been introduced to the nucleus, and finally those analogues with restrained conformations and those that are optically active. The importance of the various parameters involved in the agonist and antagonist profile of the compounds is indicated, as is the difference in the action of the chiral melatoninergics.

**Keywords:** melatonin, indole and bioisosteric derivatives, constrained polycyclic analogues, chiral melatonin analogues
