Melatonin receptor agonist

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Melatonin receptor agonist
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In Wikidata

Melatonin receptor agonists are analogues of

half-lives. Melatonin receptor agonists were developed with the melatonin structure as a model.[1]

The melatonin receptors are

clinical trials, all bind to and activate both receptor types.[1] The binding of the agonists to the receptors has been investigated since 1986, yet is still not fully understood.[1][3][4] When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes.[2][4][5][6]

History

Xenopus laevis in 1994.[7] In 1994-1995 the melatonin receptors were characterized and cloned in the human being by Reppert and colleagues.[8]

Circadin) was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years or older, for primary insomnia (poor quality of sleep).[citation needed] Products containing melatonin are available as a dietary supplement in the United States[citation needed] and Canada. In 2009 agomelatine (Valdoxan, Melitor, Thymanax) was also[clarification needed] approved in Europe and is indicated for the treatment of major depressive disorder in adults.[citation needed] Tasimelteon completed the phase III clinical trial in the United States for primary insomnia in 2010.[9] The Food and Drug Administration (FDA) granted tasimelteon orphan drug designation status for blind individuals without light perception with non-24-hour sleep–wake disorder in January the same year,[citation needed] and final FDA approval for the same purpose was achieved in January 2014 under the trade name Hetlioz.[10]

Melatonin receptors

MT1 melatonin receptor signaling
MT2 melatonin receptor signaling

In humans there are two subtypes of melatonin receptors targeted by melatonin agonists,

adipocytes.[2]

Mechanism of action

The binding of melatonin to melatonin receptors activates a few signaling pathways.

guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.[1][4]

When melatonin receptor agonists activate their receptors it causes numerous physiological processes.

phototransduction. This is not a complete list since many of the possible processes need further confirmation.[2]

Drug design and development

Receptors and the structure of melatonin are known. Therefore, researchers started to investigate modulations of the core structure to develop better agonists than melatonin; more potent, with better pharmacokinetics and longer half-life. TIK-301 (Figure 1) is an agonist of the early classes. It is very similar to melatonin and has made it to clinical trials.[1] This led to further research on the molecule, mainly substitution of the aromatic ring. Various modulations showed promising activity, especially the naphthalene ring which is present in agomelatine (Figure 1).[1][7] Other ring systems have also showed melatonin agonist activity. Amongst them are indane which is present in ramelteon (Figure 1) and the ring system of tasimelteon (Figure 1).[1][3]

Structure-activity relationship

The general structure of melatonin is the

methoxy group in position 5 (5-methoxy group) and acylaminoethyl side-chain in position 3.[1] The two side-chains are important for binding to and activating the receptors.[3] The indole ring has been evaluated at all positions by the effect of substitutions as seen in Figure 1.[1] Each position is further explained below:[1]

Position Abbreviation Action
1 R1 Possible to substitute with small groups like methyl without little changes in binding affinity. Bulky groups lower binding affinity and intrinsic activity.
2 R2 Addition of iodine, bromine and
phenyl functional groups
lead to agonists with higher binding affinity of approximately ten-fold.
3 R3 The acylaminoethyl side-chain is important, as mentioned before. In this position it is possible to control agonist and antagonist activity.
4 R4 Often involved in ring closure in melatonin agonists, although this position has been poorly investigated.
5 R5 The methoxy group is important, as mentioned before. Substitution with halogens, such as chlorine (Cl) and bromine (Br) has shown lower binding affinity. Moving the methoxy group to other positions on the indole ring, e.g. 4, 6 or 7, leads to lower binding affinity.
6 R6 Substitution leads to lower binding affinity, but this position is important for the pharmacokinetics. The main metabolite in vivo is 6-hydroxymelatonin.
7 R7 Introduction of groups at this position generally leads to lower binding affinity.
β Rβ Possible to substitute with small groups like methyl without little changes in binding affinity. Bulkier groups lower binding affinity.
TIK-301
Figure 1: Melatonin receptor agonists. The applied colors indicate the mutual properties with the general melatonin receptor agonists pharmacophore.

Binding and pharmacophore

2-Iodomelatonin was synthesized in 1986 and its radioligand, 2-[125I]-melatonin, has been useful in finding cellular targets of melatonin. Though the melatonin receptor was not characterized and cloned in the human being until 1994 it was possible to start carrying out binding studies in various tissues before that time.

tetraline, tetrahydroquinolines).[12][13] An example of approved drug with naphthalene ring is agomelatine. The aromatic ring and the ethyl side-chain hold the correct distance between those two groups, as the correct distance is the key to good binding and more important than what type of aromatic ring system the analogue contains. Therefore, it is possible to use different ring systems in melatonin receptor analogues, if the distance is right.[1][3][4] Furthermore, the aromatic ring can be substituted with different flexible scaffolds, such as phenyl-propilamides, O-phenoxy-ethylamides or N-anilino-ethylamides.[12] The ethylamide chain of these ligands has been thought having a bioactive conformation with said chain projecting outside of the indole plane and it was demonstrated by testing rigidified analogues.[14] Substituents in positions 1 or 2 of the indole scaffold projecting outside of the aromatic cycle plane increase selectivity toward the MT2 receptor, resulting in the most selective melatonin receptor ligands and simultaneously reducing receptor activation.[15][16]

The melatonin receptors consist of proteins around 40 kDa each. The MT1 receptor encodes 350 amino acids and the MT2 encodes 362 amino acids. The binding of melatonin and its analogues is now understood through X-ray crystal structures published in 2019.[17][18] The binding space for melatonin and analogues on the MT1 receptor is smaller than on the MT2.[4][18] Investigations usually focus on two binding pockets, for the two side-chains. The binding pocket of the 5-methoxy group is more investigated than the other pocket.[4][5] Researchers agree that the oxygen in the group binds to histidine (His) residues in transmembrane 5 (TM5) domain of the receptor with a hydrogen bond; His1955.46 in MT1 and His2085.46 in MT2.[3][4] Another amino acid, Val192, also participates in the binding of the 5-methoxy group by binding to the methyl portion of the group.[4] His1955.46 has also been proposed as important for receptor activation.

The binding of the N-acetyl group is more complex and less known. The important amino acids in the binding pocket for this group differ between the two receptors.

van der Waals interactions.[3] The N-acetyl binding and binding pocket, binding of the ring system and important domains are somewhat known and need further investigation.[1][3][4]

In past years, mutagenesis of residues involved in the binding site was not fully successful in the determination of the polar key contacts [13] established by the methoxy group and the ethyl-amide side chain. Asn162/1754.60 and the Gln181/194, belonging to the ECL2, bind the methoxy and the ethyl-amide groups, respectively. The importance of His195/2085.46 could be related to the receptor activation, since cryo-electron microscopy structures of the ternary complexes of the receptor show that the residues enters the binding site, near the "toogle-switch" residue Trp6.48.[6]

Carbamate insecticides target human melatonin receptors.[19]
Despite its structural similarities with melatonin, serotonin is not able to bind melatonin receptor due to the polar first amine group and the lack of an aspartate in position 3.32 within melatonin receptor orthosteric site.

Current status

There are three melatonin agonists on the market today (February 2014);

Servier and approved in Europe 2009. Tasimelteon was developed by Vanda Pharmaceuticals and completed the phase III trial in 2010. It was approved by the FDA on January 31, 2014, for the treatment of non-24-hour sleep–wake disorder in totally blind individuals.[10]

One melatonin agonist has received orphan drug designation and is going through clinical trials in the United States: TIK-301. Originally TIK-301 was developed by Eli Lilly and Company and called LY-156,735, it wasn't until July 2007 that Tikvah Pharmaceuticals took over the development and named it TIK-301. It is now in phase II trials and has been since 2002.[1][20][unreliable source?] In July 2010 in Europe, prolonged-release melatonin (Circadin, Neurim Pharmaceuticals) was approved for use for 13 weeks for insomnia patients over 55 years old.[21] Additionally, Neurim Pharmaceuticals reported the results of a positive phase II trial of its investigational compound piromelatine (Neu-P11) in February 2013.[22]

No antagonists or selective ligands are currently reported in clinical studies.

Several characteristics of approved receptor agonists and orphan drug agonists[1][8][23][24]
Circadin Ramelteon Agomelatine Tasimelteon TIK-301
Binding affinity — MT1: Ki = 0.014 nM
MT2: Ki = 0.045 nM		 MT1: Ki = 0.062 nM
MT2: Ki = 0.268 nM
5-HT2C: IC50 = 270 nM*		 MT1: Ki = 0.35 nM
MT2: Ki = 0.17 nM		 MT1: Ki = 0.081nM
MT2: Ki = 0.042 nM
Bioavailability 15% < 2% < 5% not determined in humans —
Half-life 40–50 min
3.5–4 h (terminal)		 1–2 h 1–2 h 0.9–1.7 h
0.8–5.9 h (terminal)		 —
Protein binding 60% 82% 95% 89–90% —
Volume of distribution — 73.6 L 35 L 56–126 L —
Company Neurim Pharmaceuticals Takeda Pharmaceutical Company Servier Vanda Pharmaceuticals Tikvah Pharmaceuticals
*Serotonin antagonist.

See also

  • TIK-301 (
    LY-156,735
    , PD-6735)

References

  1. ^
    PMID 18673165.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  2. ^
    S2CID 42549910.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  3. ^
    PMID 15357831.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  4. ^
    PMID 20605968.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  5. ^
    PMID 12628439.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  6. ^
    PMID 35075127
    .
  7. ^
    S2CID 54524999.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  8. ^
    S2CID 25430719.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  9. doi:10.1016/j.jsmc.2009.02.007.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  10. ^ a b "FDA approves Hetlioz: first treatment for non-24 hour sleep-wake disorder in blind individuals" (Press release). FDA. January 31, 2014. Archived from the original on February 2, 2014.
  11. PMID 18032103
    .
  12. ^
    PMID 32531076
    .
  13. ^
    S2CID 247295193
    .
  14. PMID 16431121
    .
  15. PMID 12672242
    .
  16. S2CID 252295726
    .
  17. ^ Stauch2019
  18. ^ a b Johansson 2019
  19. PMID 28027439
    .
  20. ^ "Future Treatments for Depression, Anxiety, Sleep Disorders, Psychosis, and ADHD". Neurotransmitter.net. 2011-06-17. Retrieved 2012-02-10.
  21. ^ "Circadin approved in the EU for treatment of Primary Insomnia in patients aged 55 or over for up to 3 months" (Press release). Neurim Pharmaceuticals. July 5, 2010. Retrieved February 19, 2020.
  22. ^ "Neurim Pharmaceuticals Announces Positive Phase 2 Clinical Trial Results of Piromelatine for the Treatment of Insomnia" (Press release). Neurim Pharmaceuticals. February 18, 2013. Retrieved February 19, 2020.
  23. ^ "Highlights of prescribing information for Hetlioz" (PDF).
  24. ^ "Tasimelteon Advisory Committee Meeting Briefing Materials" (PDF). Vanda Pharmaceuticals. November 2013. Archived from the original (PDF) on November 25, 2013.
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