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Synthetic Melatonin Receptor Agonists and Antagonists

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Andrew Tsotinis and Ioannis P. Papanastasiou

Submitted: November 13th, 2019 Reviewed: January 29th, 2020 Published: March 4th, 2020

DOI: 10.5772/intechopen.91424

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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

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, 9, 10] but characterized and described in the 1980s by using the radiolabeled 2-[125I]-iodomelatonin and 3H-melatonin ligands [11, 12]. Herein, we are reviewing the synthetic routes of 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.

Figure 1.

Regulation of melatonin production.

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2. Indole and bioisosteric derivatives

A guide of general principles has been applied throughout SARs for both melatonin receptors. The C5-OMe group of the indole ring is optimal, while the same substituent at positions 4, 6, or 7 leads to a drastic loss of affinity. However, congeners with a halogen at the 5-position do retain high affinity [13]. The relative position of the methoxy group and the N-acetylaminoethyl side chain seems to be the most important structural feature that increases the melatonin receptor binding affinity [14, 15, 16]. The syntheses of these derivatives are based on classic chemical procedures [17, 18, 19]. The indole ring could also be considered as a spacer [20, 21] with the pyrrole portion not involved in the receptor binding pocket, because it can be replaced by diverse aromatic scaffolds, such as naphthalene, benzofuran, benzothiophene, or benzocycloalkane rings [14, 22, 23]. Various congeners with substitutions in the positions 2 and 6 of melatonin have been synthesized. Substituents, like methyl, phenyl, or halogen at position 2 of melatonin, can increase receptor binding affinity by ca tenfold [24, 25, 26, 27]. The presence of an optimal N-acyl group with a 2-halogen substitution exhibits very potent affinity [28].

Interestingly, substituents on the 2-position seem to direct the N-acetylaminoethyl side chain into the optimal conformation for interaction with the receptor and increase the ligand affinity [29, 30]. 6-Substituted analogues have been prepared [31] with the aim of retarding metabolism, because melatonin is degraded rapidly in vivo, mainly in the liver, by 6-hydroxylation followed by conjugation and excretion in the urine. A halogen substituent at the 6-position reduces binding affinity nonsignificantly, while the binding affinity of 6-hydroxymelatonin is decreased by 5 to 10 times and 6-methoxymelatonin by more than 100 times [32].

One of the synthetic routes for the production of 5-methoxyindole (4) is via the Leimgruber-Batcho reaction [33], modified by Repke and Ferguson [34] (Figure 2). A successful side chain functionalization was reported by Ates-Alagoz et al. [35] using the Vilsmeier-Haack formylation reaction of 5-methoxyindole (4). On the other hand, Righi et al. [36] applied the direct C3 reductive alkylation of N-benzyl-5-methoxyindole (8), as described in Figure 2.

Figure 2.

Highlighted synthetic routes of melatonin 1.

In an attempt to map the receptor requirements, a series of phenylalkyl amides 911 were prepared and proven to exhibit the minimal structure required for the ligand recognition by melatonin receptors [16, 37, 38] (Figure 3).

Figure 3.

Phenylalkyl amides.

Some C3-modified melatonin analogues have exhibited interesting melatoninergic activities. It has been shown that small modifications in the acyl chain are able to change the binding affinity for melatonin receptors. A typical modification to increase the activity is the replacement of the acetyl by an N-butanoyl chain. Depreux et al. reported a 100-fold higher affinity of 5-methoxy-N-butanoyltryptamine than melatonin [14]. Tsotinis et al. reported that upon the appropriate functionalization at the end of the C2 side chain, the azido compounds 16 were produced, which serve as photoactivity labels, while the respective isothiocyanate compounds 17 serve as electrophilic probes (Figure 4), in order to produce adducts covalently linked to key amino acid residues of the melatonin receptor subtypes [39].

Figure 4.

C2-functionalized melatonin analogues.

Luzindole, N-acetyl-2-benzyltryptamine (21), is a selective melatonin receptor antagonist with approximately 11- to 25-fold higher affinity for the MT2 than the MT1 receptor [4]. The synthesis of luzindole, achieved through a Pictet-Spengler reaction and formation of the intermediate β-carboline 19, was first patented by Dubocovich et al. [40]. In 2008, Tsotinis et al. reported a new method of luzindole synthesis, through the C-3 indole nitroolefin 22, leading to a much higher overall yield [41] (Figure 5).

Figure 5.

Luzindole.

The benzo[b]furan nucleus can replace the indole skeleton and retain its reactivity. 5-Methoxy-3-oxo-2,3-dihydrobenzo[b]furan (25) was prepared from 4-methoxyphenol (23) by acylation with chloracetonitrile followed by cyclization [42] (Figure 6). Tasimelteon, N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl] methyl]propenamide (27), is a melatonin agonist, which bears the benzo[b]furan skeleton and was approved by the FDA, in January 2014, for the treatment of non-24 h sleep–wake disorder [43]. The starting material for the synthesis of tasimelteon is the 4-vinyl-2, 3-dihydrobenzofuran (26).

Figure 6.

Tasimelteon.

The naphthalene scaffold can also be considered as a melatonin-acting biomolecule with high affinity and potency [44, 45]. The preparation of the key intermediate in this synthesis, 2-(7-methoxy-1-naphthyl)ethanol (31), is depicted in Figure 7. Agomelatine, N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (32), was recently approved for medical use in Europe and Australia [46].

Figure 7.

Agomelatine.

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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.

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.

Figure 9.

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

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

Figure 10.

Azaindoles.

In the synthetic route to the 3a-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).

Figure 11.

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

The pharmacological evaluation has shown that 6H-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-5H-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.

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4. Chiral melatonin analogues

Some derivatives with constrained conformation also present chirality. Ramelteon is the most emblematic representative example of this class of compounds. Ramelteon, N-{2-[(8S)-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.

Figure 12.

Ramelteon.

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 N1-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, 56, 57].

Figure 13.

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

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.

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5. Conclusions

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.

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Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA. MT 1 and MT 2 melatonin receptors: Ligands, models, oligomers, and therapeutic potential. Journal of Medicinal Chemistry. 2014;57(8):3161-3185. Available from: https://pubs.acs.org/doi/10.1021/jm401343c
  2. 2. Oishi A, Cecon E, Jockers R. Melatonin receptor signaling: Impact of receptor oligomerization on receptor function. In: International Review of Cell and Molecular Biology. Cambridge, MA, United States: Elsevier; 2018. pp. 59-77. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1937644818300121
  3. 3. Gobbi G, Comai S. Sleep well. Untangling the role of melatonin MT1 and MT2 receptors in sleep. Journal of Pineal Research. 2019;66(3):e12544. Available from: http://doi.wiley.com/10.1111/jpi.12544
  4. 4. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacological Reviews. 2010;62(3):343-380. Available from: http://pharmrev.aspetjournals.org/lookup/doi/10.1124/pr.110.002832
  5. 5. Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang X-P, et al. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature. 2019;569(7755):284-288. Available from: http://www.nature.com/articles/s41586-019-1141-3
  6. 6. Johansson LC, Stauch B, McCorvy JD, Han GW, Patel N, Huang X-P, et al. XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity. Nature. 2019;569(7755):289-292. Available from: http://www.nature.com/articles/s41586-019-1144-0
  7. 7. Tan D-X, Manchester LC, Terron MP, Flores LJ, Tamura H, Reiter RJ. Melatonin as a naturally occurring co-substrate of quinone reductase-2, the putative MT 3 melatonin membrane receptor: Hypothesis and significance. Journal of Pineal Research. 2007;43(4):317-320. Available from: http://doi.wiley.com/10.1111/j.1600-079X.2007.00513.x
  8. 8. Ebisawa T, Karne S, Lerner MR, Reppert SM. Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proceedings of the National Academy of Sciences. 1994;91(13):6133-6137. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.91.13.6133
  9. 9. Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: The Mel1b melatonin receptor. Proceedings of the National Academy of Sciences. 1995;92(19):8734-8738. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.92.19.8734
  10. 10. Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994;13(5):1177-1185. Available from: https://linkinghub.elsevier.com/retrieve/pii/0896627394900558
  11. 11. Vakkuri O, Leppäluoto J, Vuolteenaho O. Development and validation of a melatonin radioimmunoassay using radioiodinated melatonin as tracer. Acta Endocrinologica. 1984;106(2):152-157. Available from: https://eje.bioscientifica.com/view/journals/eje/106/2/acta_106_2_002.xml
  12. 12. Vaněček J, Pavlík A, Illnerová H. Hypothalamic melatonin receptor sites revealed by autoradiography. Brain Research. 1987;435(1-2):359-362. Available from: https://linkinghub.elsevier.com/retrieve/pii/0006899387916258
  13. 13. Mor M, Rivara S, Silva C, Bordi F, Plazzi PV, Spadoni G, et al. Melatonin receptor ligands: Synthesis of New melatonin derivatives and comprehensive comparative molecular field analysis (CoMFA) study. Journal of Medicinal Chemistry. 1998;41(20):3831-3844. Available from: https://pubs.acs.org/doi/10.1021/jm9810093
  14. 14. Depreux P, Lesieur D, Mansour HA, Morgan P, Howell HE, Renard P, et al. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Journal of Medicinal Chemistry. 1994;37(20):3231-3239. Available from: https://pubs.acs.org/doi/abs/10.1021/jm00046a006
  15. 15. Langlois M, Bremont B, Shen S, Poncet A, Andrieux J, Sicsic S, et al. Design and synthesis of new naphthalenic derivatives as ligands for 2-[125I] iodomelatonin binding sites. Journal of Medicinal Chemistry. 1995;38(12):2050-2060. Available from: https://pubs.acs.org/doi/abs/10.1021/jm00012a004
  16. 16. Garratt PJ, Travard S, Vonhoff S, Tsotinis A, Sugden D. Mapping the melatonin receptor. 4. Comparison of the binding affinities of a series of substituted Phenylalkyl amides. Journal of Medicinal Chemistry. 1996;39(9):1797-1805. Available from: http://pubs.acs.org/doi/abs/10.1021/jm9508189
  17. 17. Plieninger H. The chemistry of indoles. Organic chemistry, a series of monographs, Vol. 18. Von R. J. Sundberg. Academic Press, New York–London 1970. 1. Aufl., X, 489 S., s229/—. Angewandte Chemie. 1971;83(9):338-338. Available from: http://doi.wiley.com/10.1002/ange.19710830918
  18. 18. Gribble GW. Recent developments in indole ring synthesis—Methodology and applications. Contemporary Organic Synthesis. 1994;1(3):145-172. Available from: http://xlink.rsc.org/?DOI=CO9940100145
  19. 19. Gribble GW. Recent developments in indole ring synthesis—Methodology and applications. Journal of the Chemical Society, Perkin Transactions 1. 2000;1(7):1045-1075. Available from: http://xlink.rsc.org/?DOI=a909834h
  20. 20. Frohn MA, Seaborn CJ, Johnson DW, Phillipou G, Seamark RF, Matthews CD. Structure - activity relationship of melatonin analogues. Life Sciences. 1980;27(22):2043-2046. Available from: https://linkinghub.elsevier.com/retrieve/pii/0024320580904828
  21. 21. Heward CB, Hadley ME. Structure-activity relationships of melatonin and related indoleamines. Life Sciences. 1975;17(7):1167-1177. Available from: https://linkinghub.elsevier.com/retrieve/pii/0024320575903409
  22. 22. Leclerc V, Fourmaintraux E, Depreux P, Lesieur D, Morgan P, Howell HE, et al. Synthesis and structure–activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Bioorganic & Medicinal Chemistry. 1998;6(10):1875-1887. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0968089698001473
  23. 23. Fukatsu K, Uchikawa O, Kawada M, Yamano T, Yamashita M, Kato K, et al. Synthesis of a novel series of benzocycloalkene derivatives as melatonin receptor agonists. Journal of Medicinal Chemistry. 2002;45(19):4212-4221. Available from: https://pubs.acs.org/doi/10.1021/jm020114g
  24. 24. Spadoni G, Mor M, Tarzia G. Structure-affinity relationships of indole-based melatonin analogs. Neurosignals. 1999;8(1-2):15-23. Available from: https://www.karger.com/Article/FullText/14564
  25. 25. Garratt PJ, Jones R, Rowe SJ, Sugden D. Mapping the melatonin receptor. 1. The 5-methoxyl group of melatonin is not an essential requirement for biological activity. Bioorganic & Medicinal Chemistry Letters. 1994;4(13):1555-1558. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960894X01805655
  26. 26. Garratt PJ, Vonhoff S, Rowe SJ, Sugden D. Mapping the melatonin receptor. 2. Synthesis and biological activity of indole derived melatonin analogues with restricted conformations of the C-3 amidoethane side chain. Bioorganic & Medicinal Chemistry Letters. 1994;4(13):1559-1564. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960894X01805667
  27. 27. Garratt PJ, Jones R, Tocher DA, Sugden D. Mapping the melatonin receptor. 3. Design and synthesis of melatonin agonists and antagonists derived from 2-Phenyltryptamines. Journal of Medicinal Chemistry. 1995;38(7):1132-1139. Available from: https://pubs.acs.org/doi/abs/10.1021/jm00007a010
  28. 28. Sugden D, Rowe SJ. 2-Iodo-N-butanoyl-5-methoxytryptamine: A potent melatonin receptor agonist. Pharmacology Communications. 1994;4:267-276
  29. 29. Mathé-Allainmat M, Gaudy F, Sicsic S, Dangy-Caye A-L, Shen S, Brémont B, et al. Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as New Conformationally restricted ligands for melatonin receptors. Journal of Medicinal Chemistry. 1996;39(16):3089-3095. Available from: https://pubs.acs.org/doi/10.1021/jm960219h
  30. 30. Spadoni G, Balsamini C, Diamantini G, Di Giacomo B, Tarzia G, Mor M, et al. Conformationally restrained melatonin analogues: Synthesis, binding affinity for the melatonin receptor, evaluation of the biological activity, and molecular Modeling study. Journal of Medicinal Chemistry. 1997;40(13):1990-2002. Available from: https://pubs.acs.org/doi/10.1021/jm960651z
  31. 31. Flaugh ME, Crowell TA, Clemens JA, Sawyer BD. Synthesis and evaluation of the antiovulatory activity of a variety of melatonin analogs. Journal of Medicinal Chemistry. 1979;22(1):63-69. Available from: https://pubs.acs.org/doi/abs/10.1021/jm00187a015
  32. 32. Sugden D, Chong NWS, DFV L. Structural requirements at the melatonin receptor. British Journal of Pharmacology. 1995;114(3):618-623. Available from: http://doi.wiley.com/10.1111/j.1476-5381.1995.tb17184.x
  33. 33. Li JJ. Batcho–Leimgruber indole synthesis. In: Name Reactions. Cham: Springer International Publishing; 2014. pp. 34-35. Available from: http://link.springer.com/10.1007/978-3-319-03979-4_17
  34. 34. Repke DB, Ferguson WJ. Psilocin analogs. III. Synthesis of 5-methoxy- and 5-hydroxy-1,2,3,4-tetrahydro-9 H-pyrido[3,4-b]indoles. Journal of Heterocyclic Chemistry. 1982;19(4):845-848. Available from: http://doi.wiley.com/10.1002/jhet.5570190428
  35. 35. Ates-Alagoz Z, Buyukbingol Z, Buyukbingol E. Synthesis and antioxidant properties of some indole ethylamine derivatives as melatonin analogs. Die Pharmazie. 2005 Sep;60(9):643-647
  36. 36. Righi M, Topi F, Bartolucci S, Bedini A, Piersanti G, Spadoni G. Synthesis of tryptamine derivatives via a direct, one-pot reductive alkylation of indoles. The Journal of Organic Chemistry. 2012;77(14):6351-6357. Available from: https://pubs.acs.org/doi/10.1021/jo3010028
  37. 37. Hu Y, Ho MKC, Chan KH, New DC, Wong YH. Synthesis of substituted N-[3-(3-methoxyphenyl)propyl] amides as highly potent MT2-selective melatonin ligands. Bioorganic & Medicinal Chemistry Letters. 2010;20(8):2582-2585. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960894X10002842
  38. 38. Tsotinis A, Kompogennitaki R, Papanastasiou I, Garratt PJ, Bocianowska A, Sugden D. Fluorine substituted methoxyphenylalkyl amides as potent melatonin receptor agonists. Medicinal Chemistry Communications. 2019;10(3):460-464. Available from: https://pubs.rsc.org/en/content/articlelanding/2019/md/c8md00604k
  39. 39. Tsotinis A, Afroudakis PA, Davidson K, Prashar A, Sugden D. Design, synthesis, and melatoninergic activity of New Azido- and isothiocyanato-substituted indoles. Journal of Medicinal Chemistry. 2007;50(25):6436-6440. Available from: https://pubs.acs.org/doi/10.1021/jm7010723
  40. 40. Dubocovich ML, Rajadhyaksha VJ, Helmy AA. 2-Aryl N-acetyltryptamines and Process of Preparing Such. US 528334; 1994
  41. 41. Tsotinis A, Afroudakis P. Melatonin receptor antagonist luzindole: A facile new synthesis. Letters in Organic Chemistry. 2008;5(6):507-509. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1570-1786&volume=5&issue=6&spage=507
  42. 42. Hammond ML, Zambias RA, Chang MN, Jensen NP, McDonald J, Thompson K, et al. Antioxidant-based inhibitors of leukotriene biosynthesis. The discovery of 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3-yl]-2,3-dihydro-5-benzofuranol, a potent topical antiinflammatory agent. Journal of Medicinal Chemistry. 1990;33(3):908-918. Available from: https://pubs.acs.org/doi/abs/10.1021/jm00165a005
  43. 43. Hardeland R. Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders. Current Opinion in Investigational Drugs. 2009;10(7):691-701
  44. 44. Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P, Pfeiffer B, et al. Novel naphthalenic ligands with high affinity for the melatonin receptor. Journal of Medicinal Chemistry. 1992;35(8):1484-1486. Available from: https://pubs.acs.org/doi/abs/10.1021/jm00086a018
  45. 45. Li P-K, Chu G-H, Gillen ML, Parekh T, Witt-Enderby PA. The development of a charged melatonin receptor ligand. Bioorganic & Medicinal Chemistry Letters. 1997;7(18):2409-2414. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960894X97004447
  46. 46. Norman TR, Olver JS. Agomelatine for depression: Expanding the horizons? Expert Opinion on Pharmacotherapy. 2019;20(6):647-656. Available from: https://www.tandfonline.com/doi/full/10.1080/14656566.2019.1574747
  47. 47. Tsotinis A, Panoussopoulou M, Sivananthan S, Sugden D. Synthesis of new tricyclic melatoninergic ligands. Il Farmaco. 2001;56(9):725-729. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014827X01011259
  48. 48. El Kazzouli S, Griffon du Bellay A, Berteina-Raboin S, Delagrange P, Caignard D-H, Guillaumet G. Design and synthesis of 2-phenylimidazo[1,2-a]pyridines as a novel class of melatonin receptor ligands. European Journal of Medicinal Chemistry. 2011;46(9):4252-4257. Available from: https://linkinghub.elsevier.com/retrieve/pii/S022352341100506X
  49. 49. Viaud-Massuard M-C, Mazéas D, Guillaumet G. Synthesis of new melatoninergic ligands including azaindole moiety. Heterocycles. 1999;50(2):1065. Available from: http://www.heterocycles.jp/newlibrary/libraries/abst/07243
  50. 50. Jeanty M, Suzenet F, Delagrange P, Nosjean O, Boutin JA, Caignard DH, et al. Design and synthesis of 1-(2-alkanamidoethyl)-6-methoxy-7-azaindole derivatives as potent melatonin agonists. Bioorganic & Medicinal Chemistry Letters. 2011;21(8):2316-2319. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960894X11002812
  51. 51. Faust R, Garratt PJ, Jones R, Yeh L-K, Tsotinis A, Panoussopoulou M, et al. Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6H-isoindolo[2,1-a]indoles, 5,6-dihydroindolo[2,1-a]isoquinolines, and 6,7-dihydro-5H-benzo[c]azepino[2,1-a]indoles. Journal of Medicinal Chemistry. 2000;43(6):1050-1061
  52. 52. Uchikawa O, Fukatsu K, Tokunoh R, Kawada M, Matsumoto K, Imai Y, et al. Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. Journal of Medicinal Chemistry. 2002;45(19):4222-4239. Available from: https://pubs.acs.org/doi/10.1021/jm0201159
  53. 53. Xiao S, Chen C, Li H, Lin K, Zhou W. A novel and practical synthesis of Ramelteon. Organic Process Research & Development. 2015;19(2):373-377. Available from: https://pubs.acs.org/doi/10.1021/op500386g
  54. 54. Sugden D, Davies DJ, Garratt PJ, Jones R, Vonhoff S. Radioligand binding affinity and biological activity of the enantiomers of a chiral melatonin analogue. European Journal of Pharmacology. 1995;287(3):239-243. Available from: https://linkinghub.elsevier.com/retrieve/pii/0014299995004890
  55. 55. Tsotinis A, Panoussopoulou M, Hough K, Sugden D. Synthesis and biological evaluation of new β,β′-disubstituted 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl ethylamido melatoninergic ligands. European Journal of Pharmaceutical Sciences. 2003;18(5):297-304. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0928098703000204
  56. 56. Tsotinis A, Panoussopoulou M, Eleutheriades A, Davidson K, Sugden D. Design, synthesis and melatoninergic activity of new unsubstituted and β,β′-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides. European Journal of Medicinal Chemistry. 2007;42(7):1004-1013. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0223523407000372
  57. 57. Tsotinis A, Vlachou M, Papahatjis D, Nikas S, Sugden D. An efficient synthesis of simple β,β-Cyclobisalkylated Melatoninergic Phenylalkylamides. Letters in Organic Chemistry 2007;4(2):92-95. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1570-1786&volume=4&issue=2&spage=92
  58. 58. Tsotinis A, Vlachou M, Papahatjis DP, Calogeropoulou T, Nikas SP, Garratt PJ, et al. Mapping the melatonin receptor. 7. Subtype selective ligands based on β-substituted N-Acyl-5-methoxytryptamines and β-substituted N-Acyl-5-methoxy-1-methyltryptamines. Journal of Medicinal Chemistry. 2006;49(12):3509-3519. doi: 10.1021/jm0512544

Written By

Andrew Tsotinis and Ioannis P. Papanastasiou

Submitted: November 13th, 2019 Reviewed: January 29th, 2020 Published: March 4th, 2020