**1. Introduction**

Melatonin (*N*-acetyl-5-methoxytryptamine **1**) is a hormone ubiquitously distributed in a variety of organisms, such as bacteria, unicellular algae, fungi, plants, vertebrates, and mammalians [1]. Melatonin is mainly known to regulate circadian rhythms by synchronization to environmental cues but participates also in diverse important physiological processes, such as regulation of the visual functions, glucose metabolism, and immune functions (**Figure 1**) [2]. The functions of melatonin are modulated through its binding to G protein-coupled receptors (GPCRs), which activate signaling pathways, as a cascade effect [3]. Up to date, two different types of melatonin receptors have been described in mammals: type 1A (MT1) and type 1B (MT2). Both receptors are located in many regions in the central nervous system and in peripheral tissues as well [4]. X-ray free electron laser (XFEL) studies have recently revealed that MT1 binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181 [5]. Comparison of the structures of MT2 and MT1 indicated that, despite conservation of the orthosteric ligand binding site residues, there are significant conformational variations between both melatonin receptor subtypes, which justify the selectivity between the two subtypes [6]. Melatonin was proven to bind to one more co-substrate binding site (MT3), which is a quinone reductase-2 [7]. Melatonin receptors had been cloned in 1990s [8–10] but characterized and described in the 1980s by using the radiolabeled 2-[125I]-iodomelatonin and 3 H-melatonin ligands [11, 12]. Herein, we are reviewing the synthetic routes of

**Figure 1.** *Regulation of melatonin production.*

the main indole and bioisosteric aromatic nucleus derivatives: first, the conformationally restricted; the active chiral compounds second; and the derivatives with substituted 3-side chains third.
