Synthetic Melatonin Receptor Agonists and Antagonists

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.

Experimental Data on the Role of Melatonin in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…It is hypothesized that new compounds that act as specific melatonin agonists or antagonists will contribute to a better understanding of melatonin’s mechanism of action [ 29 ]. Melatonin analogues (agonists and antagonists) differ in their chemical structure and affinity for melatonin receptors [ 94 ]. Currently, powerful, lipophilic, non-selective MT1/MT2 high-exposure agonists in the brain, such as Ramelteon, Agomelatine, Tazimelteon, and prolonged-release melatonin (Circadin), are approved for the treatment of insomnia, depression, and circadian rhythm sleep–wake disorders [ 95 ].…”

Mapping the Melatonin Receptor. 8. Selective MT2 Agonists Derived from 5,6‐Dihydroindolo[2,1‐a]isoquinolines and Related Systems

“…[9] There have been numerous studies directed towards the understanding of how melatonin binds to and activates these receptors using both indole and non-indole derivatives. [27][28][29][30][31] The 5-methoxyl group has been shown to be important for binding to the receptor, but it is not an essential requirement for agonist activity [32] and the indole nitrogen does not serve any obvious binding function and can be omitted in active analogues. [33][34][35][36][37][38] The active conformation of the 3-ethanamine side chain has been studied from conformationally restricted indole [37,39] and non-indole analogues.…”