Melatonin Receptor Agonists and Antagonists

**3**

and 3

**Chapter 1**

**Abstract**

analogues, chiral melatonin analogues

**1. Introduction**

Synthetic Melatonin Receptor

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

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

H-melatonin ligands [11, 12]. Herein, we are reviewing the synthetic routes of

Agonists and Antagonists

*Andrew Tsotinis and Ioannis P. Papanastasiou*
