**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 [14–16]. The syntheses of these derivatives are based on classic chemical procedures [17–19]. 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

**5**

**Figure 2.**

*Highlighted synthetic routes of melatonin 1.*

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

substitution exhibits very potent affinity [28].

and 6-methoxymelatonin by more than 100 times [32].

ligand recognition by melatonin receptors [16, 37, 38] (**Figure 3**).

linked to key amino acid residues of the melatonin receptor subtypes [39].

5-methoxyindole (**8**), as described in **Figure 2**.

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 [24–27]. The presence of an optimal *N*-acyl group with a 2-halogen

Interestingly, substituents on the 2-position seem to direct the *N*-acetylaminoethyl

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-

In an attempt to map the receptor requirements, a series of phenylalkyl amides **9**–**11** were prepared and proven to exhibit the minimal structure required for the

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

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

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

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

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

the main indole and bioisosteric aromatic nucleus derivatives: first, the conformationally restricted; the active chiral compounds second; and the derivatives with

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 [14–16]. The syntheses of these derivatives are based on classic chemical procedures [17–19]. 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

**4**

**Figure 1.**

substituted 3-side chains third.

*Regulation of melatonin production.*

**2. Indole and bioisosteric derivatives**

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 [24–27]. 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**.

In an attempt to map the receptor requirements, a series of phenylalkyl amides **9**–**11** were prepared and proven to exhibit the minimal structure required for the ligand recognition by melatonin receptors [16, 37, 38] (**Figure 3**).

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].

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

**Figure 2.** *Highlighted synthetic routes of melatonin 1.*

**Figure 3.** *Phenylalkyl amides.*

**Figure 4.** *C2-functionalized melatonin analogues.*

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**).

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**).

**7**

**Figure 8.**

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

4-vinyl-2, 3-dihydrobenzofuran (**26**).

**Figure 6.** *Tasimelteon.*

**Figure 7.** *Agomelatine.*

**3. Constrained polycyclic derivatives**

(**36**) [47] is illustrated in **Figure 8**.

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

approved for medical use in Europe and Australia [46].

Tasimelteon, *N*-[[(1*R*,2*R*)-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

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

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

**Figure 5.** *Luzindole.*

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

**Figure 6.** *Tasimelteon.*

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

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

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**).

**6**

**Figure 5.** *Luzindole.*

yield [41] (**Figure 5**).

*C2-functionalized melatonin analogues.*

**Figure 3.** *Phenylalkyl amides.*

**Figure 4.**

**Figure 7.** *Agomelatine.*

Tasimelteon, *N*-[[(1*R*,2*R*)-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**).

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].
