**3. Constrained polycyclic derivatives**

Tricyclic and even larger constrained derivatives have been investigated for their melatoninergic potency. The synthesis of 6,7,8,9-tetrahydropyridino[1,2-*a*]indole (**36**) [47] is illustrated in **Figure 8**.

**Figure 8.** *6,7,8,9-Tetrahydropyridino[1,2-a]indole.*

**Figure 9.** *1,3,4,5-Tetrahydro[cd]indole.*

**9**

*Synthetic Melatonin Receptor Agonists and Antagonists DOI: http://dx.doi.org/10.5772/intechopen.91424*

*Isoindolo[2,1-a]indoles and benzo[*c*]azepeno[2,1-a]indoles.*

The 3-substituted 1,3,4,5-tetrahydro[*cd*]indoles exhibit higher melatonin receptor affinity than their more constrained congeners [30]. The key intermediate ketone **38** was obtained upon cyclization of the carboxylic acid **37** with polyphosphoric acid. As shown in **Figure 9**, the ketone **38** was converted to the corresponding cyanide **39**, in two steps. The latter gave then the respective acetamide **40**, and the final tricyclic adduct **41** was prepared by ester hydrolysis followed by decarboxylation of the cor-

Azaindoles have also been proven to exhibit melatoninergic potency. Some melatonin analogues based on 3*a*-aza-, 4-aza-, 6-aza-, and 7-azaindole cores are

In the synthetic route to the 3*a*-azamelatonin analogue **49**, El Kazzouli et al. [48] reported the treatment of 2-amino-5-bromopyridine (**42**) with 2-bromoacetone and the use of ethyl 2-azidoacetate for the formation of the key intermediate ester **45**. In the synthesis of 3-substituted-4-azaindole **49**, Mazeas et al. [49] have used 2-methoxy-5-nitropyridine (**50**), as starting material, and standard chemistry procedures. The 4-azaindole analogue **50** was proven to be a stronger agonist than melatonin at both melatonin receptors [50]. The preparation of 6-azamelatonin derivative **61** involves the Sonogashira reaction, as reported in the literature [49]. Finally, the 7-azamelatonin congener **67** presents promising melatoninergic potential [49].

The isoindolo[2,1-*a*]indoles and benzo[*c*]azepeno[2,1-*a*]indoles were prepared by Tsotinis et al. [51]. The appropriate *N*-acetyl tryptamine was coupled with the respective dibromide **68**, and the derived *N*-alkyl indole **70** was then cyclized in the

The pharmacological evaluation has shown that 6*H*-isoindolo[2,1-*a*]indoles (**71a**) are agonists, while the 5,6-dihydroindolo[2,1-*a*]isoquinolines (**71b**) are partial agonists/antagonists, and the 6,7-dihydro-5*H*-benzo[*c*]azepino[2,1-*a*]indoles (**71c**) are antagonists. Thus, the size of the linker between the phenyl ring and the pyrrole nitrogen atom serves as a switch pharmacological probe, spanning from agonist to

Some derivatives with constrained conformation also present chirality. Ramelteon is the most emblematic representative example of this class of

responding acid in boiling quinoline in the presence of copper powder.

presence of Pd(PPh3)4 to afford the desired products **71 (Figure 11)**.

described in **Figure 10**.

**Figure 11.**

antagonist melatoninergic action.

**4. Chiral melatonin analogues**

**Figure 10.** *Azaindoles.*

*Synthetic Melatonin Receptor Agonists and Antagonists DOI: http://dx.doi.org/10.5772/intechopen.91424*

#### **Figure 11.**

*Melatonin - The Hormone of Darkness and Its Therapeutic Potential and Perspectives*

**8**

**Figure 10.** *Azaindoles.*

**Figure 9.**

*1,3,4,5-Tetrahydro[cd]indole.*

*Isoindolo[2,1-a]indoles and benzo[*c*]azepeno[2,1-a]indoles.*

The 3-substituted 1,3,4,5-tetrahydro[*cd*]indoles exhibit higher melatonin receptor affinity than their more constrained congeners [30]. The key intermediate ketone **38** was obtained upon cyclization of the carboxylic acid **37** with polyphosphoric acid. As shown in **Figure 9**, the ketone **38** was converted to the corresponding cyanide **39**, in two steps. The latter gave then the respective acetamide **40**, and the final tricyclic adduct **41** was prepared by ester hydrolysis followed by decarboxylation of the corresponding acid in boiling quinoline in the presence of copper powder.

Azaindoles have also been proven to exhibit melatoninergic potency. Some melatonin analogues based on 3*a*-aza-, 4-aza-, 6-aza-, and 7-azaindole cores are described in **Figure 10**.

In the synthetic route to the 3*a*-azamelatonin analogue **49**, El Kazzouli et al. [48] reported the treatment of 2-amino-5-bromopyridine (**42**) with 2-bromoacetone and the use of ethyl 2-azidoacetate for the formation of the key intermediate ester **45**. In the synthesis of 3-substituted-4-azaindole **49**, Mazeas et al. [49] have used 2-methoxy-5-nitropyridine (**50**), as starting material, and standard chemistry procedures. The 4-azaindole analogue **50** was proven to be a stronger agonist than melatonin at both melatonin receptors [50]. The preparation of 6-azamelatonin derivative **61** involves the Sonogashira reaction, as reported in the literature [49]. Finally, the 7-azamelatonin congener **67** presents promising melatoninergic potential [49].

The isoindolo[2,1-*a*]indoles and benzo[*c*]azepeno[2,1-*a*]indoles were prepared by Tsotinis et al. [51]. The appropriate *N*-acetyl tryptamine was coupled with the respective dibromide **68**, and the derived *N*-alkyl indole **70** was then cyclized in the presence of Pd(PPh3)4 to afford the desired products **71 (Figure 11)**.

The pharmacological evaluation has shown that 6*H*-isoindolo[2,1-*a*]indoles (**71a**) are agonists, while the 5,6-dihydroindolo[2,1-*a*]isoquinolines (**71b**) are partial agonists/antagonists, and the 6,7-dihydro-5*H*-benzo[*c*]azepino[2,1-*a*]indoles (**71c**) are antagonists. Thus, the size of the linker between the phenyl ring and the pyrrole nitrogen atom serves as a switch pharmacological probe, spanning from agonist to antagonist melatoninergic action.

## **4. Chiral melatonin analogues**

Some derivatives with constrained conformation also present chirality. Ramelteon is the most emblematic representative example of this class of

**Figure 12.** *Ramelteon.*

**Figure 13.**

*Examples of chiral melatoninergic analogues and side chain conformationally constrained tricyclic derivatives 83 and 84.*

compounds. Ramelteon, *N*-{2-[(8*S*)-1,6,7,8-tetrahydro-2H-indeno[5,4-*b*]furan-8-yl]ethyl}propanamide (**76**) [52], is a melatonin analogue approved by the FDA as a sedative-hypnotic. The following synthetic route [53], illustrated in **Figure 12**, uses dibenzoyl-*L*-tartaric acid as an acid to form the salt at the end of hydrogenation and as the resolution agent as well.

Most of these chiral derivatives are prepared as racemates and, then, in some cases, resolved. The racemate mixture of enantiomers provides an initial estimation of the biology of these compounds, although asymmetric syntheses may then be required if one of the enantiomers exhibits a selective result. Substituents on the 3-side chain, particularly at the *β*-position, present a preference for the active conformation. This hypothesis has been investigated by assessing the melatoninergic potency of various compounds which bear in their side chain small to large substituents. An example of *α*- and *β*-methyl side chain functionalized molecules with enhanced activity is the *N*1-phenethyl-substituted indole derivatives **79** and **82** [54]. The characteristic steps of the synthesis of these probes are illustrated in **Figure 13**. Similar results, in terms of activities and related conformation, have been obtained for the analogues **83**, **84**, and **85** [55–57].

**11**

*Synthetic Melatonin Receptor Agonists and Antagonists DOI: http://dx.doi.org/10.5772/intechopen.91424*

The authors declare no conflict of interest.

Andrew Tsotinis\* and Ioannis P. Papanastasiou

provided the original work is properly cited.

\*Address all correspondence to: tsotinis@pharm.uoa.gr

Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Sciences, National and Kapodistrian University of Athens, Athens, Greece

28-fold selectivity for the MT2 receptor.

**5. Conclusions**

**Conflict of interest**

**Author details**

The *β*-methyl, *N*-methyl-substituted melatonin derivative **86** was prepared and resolved by chiral HPLC [58]. The (+) enantiomer has a tenfold higher potency in pigment aggregation in the *Xenopus laevis* protocol, while the (−) enantiomer has a

A selection of key melatoninergic derivatives was reported herein. We pointed out the synthetic routes towards these melatonin analogues, first of the aromatic nucleus, then of the functionalities that have been introduced to the nucleus, and finally of those analogues with restrained conformations and those that are optically active. Much more needs to be explored about the variant functions of melatonin and through which receptor type they exert their action. The range of small molecules having agonist or antagonist effects on the melatonin receptors is large, and new scaffolds keep appearing as drug candidates in different treatments. This work is hoped to assist those seeking to explore the melatonin and melatoninergic field.

The *β*-methyl, *N*-methyl-substituted melatonin derivative **86** was prepared and resolved by chiral HPLC [58]. The (+) enantiomer has a tenfold higher potency in pigment aggregation in the *Xenopus laevis* protocol, while the (−) enantiomer has a 28-fold selectivity for the MT2 receptor.
