Design of subtype selective melatonin receptor agonists and antagonists

Sugden, David; Yeh, Li-Kuan; Teh, Muy-Teck

doi:10.1051/rnd:19990306

Cited by 56 publications

(28 citation statements)

References 23 publications

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“…These compounds played a key role in the definition of pharmacophore models for MTr agonists. A conformationally constrained structure can also be found in the tetracyclic agonist IIK7 [91,92], where a bridging methylene between a 2-phenyl ring and the indole nitrogen provided a rigid derivative of 2Ph-MLT, endowed with agonist activity and MT 2 selectivity.…”

Section: Melatonin Derivatives and Early Classes Of Agonistsmentioning

confidence: 99%

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

Rivara¹,

Mor²,

Bedini³

et al. 2008

CTMC

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Melatonin (N-acetyl-5-methoxytryptamine) is synthesized and released by the pineal gland following a circadian rhythm characterized by high levels during the night. It shows several pharmacological effects on diverse cellular and animal models, mainly related to either its antioxidant activity or to its ability to activate specific receptors (MTr). Melatonin is widely used as a self-administered food additive, but its therapeutic potential needs more investigation and is hampered by its poor pharmacokinetics. This review will focus on the medicinal chemistry of agonist ligands of the two human GPCRs MT(1) and MT(2) melatonin receptors. The recent introduction of ramelteon, a non-selective MT(1)/MT(2) agonist for the treatment of insomnia, and the advancement to clinical trials of other MTr agonists have renewed interest for different classes of compounds endowed with this activity. Several chemical classes of MTr agonists are described in the literature, generally characterized by an indole, or an indole bioisostere, carrying an amide side chain and a methoxy group, or substituents with similar stereoelectronic features. Abundant information is available for non-selective MT(1)/MT(2) ligands, and several molecular models, both ligand- and receptor-based, have been proposed to rationalize their structure activity relationships. Fewer classes of selective agonists have been reported in the literature, and they could help clarifying the physiological role of the two receptor subtypes. A brief discussion on the therapeutic potential of this class of compounds is based on the clinical data available for the agonists ramelteon, agomelatine, beta-methyl-6-chloromelatonin (TIK-301) and VEC-162.

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Section: Melatonin Derivatives and Early Classes Of Agonistsmentioning

confidence: 99%

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

Rivara¹,

Mor²,

Bedini³

et al. 2008

CTMC

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“…Luzindole and 4P-PDOT competitively block MT 1 melatonin receptors at concentrations of 300 nM or more, and both act as inverse agonists in systems endowed with constitutively active MT 1 receptors (17–19). N -butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)-ethanamine (IIK7) is a selective MT 2 melatonin receptor agonist at recombinant hMT 2 receptors with an affinity ratio of approximately 90 when compared with hMT 1 (20). However, its affinity for the mouse MT 2 receptor is 1,000-fold higher than for the MT 1 receptor (21), suggesting considerable species differences in melatonin receptor pharmacology.…”

Section: Introductionmentioning

confidence: 99%

MT₁ and MT₂ Melatonin Receptors: A Therapeutic Perspective

Liu

Clough

Hutchinson

et al. 2016

Annu. Rev. Pharmacol. Toxicol.

509

380

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Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein–coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.

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“…A selection of MT 2 -selective agonists developed in the 1990s is displayed in Figure 3. The most selective agonist was IIK7 18, exhibiting a 90-fold higher binding affinity and 40-fold higher intrinsic activity (inhibiting forskolin-stimulated cAMP production in NIH3T3 cells) for the MT 2 subtype than for the MT 1 subtype [66]. 6-Chloromelatonin 19 and 6-methoxymelatonin 20 had both about 60-fold higher affinity for the MT 2 than for the MT 1 subtype at human recombinant receptors expressed in COS-7 cells [19].…”

Section: Subtype-selective Melatonin Receptor Ligands Developed In Thmentioning

confidence: 99%

“…Some 5-methoxy analogues of melatonin with ring-incorporated tertiary amide structures were also reported to be melatonin receptor antagonists [19]. Another agent containing the 5-methoxy group is the tetracyclic compound K-185 27 ( Figure 4); it is an indolic MT 2 -selective antagonist, which is derived from the agonist IIK7 18 by extension of the linkage between the indole nitrogen and the 2-phenyl ring from 1 to 3 carbons [66]. In binding assays at human MT 1 and MT 2 receptors expressed in NIH-3T3 cells, K185 was 140-fold selective for the MT 2 subtype.…”

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confidence: 99%

Recent Advances in Melatonin Receptor Ligands

Zlotos

2005

Archiv der Pharmazie

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Melatonin is a hormone exerting its multiple actions mainly through two G-protein-coupled receptors MT(1) and MT(2). Exploring the physiological role of each of these subtypes requires subtype selective MT(1) and MT(2) ligands. While several MT(2)-selective ligands were developed in the 1990s, no selective agonists and antagonists for the MT(1) subtype were described. The present article reviews mela toninergic ligands developed in the current millennium focusing on subtype selective agents and on drug candidates. Notable compounds are the MT(1)-selective agonists 35 and 134, MT(1)-selective antagonists 117 and 131, MT(2)-selective agonists 58, 70, 79, 97 and 125, MT(2)-selective antagonists 27, 73 and 119, and the highly potent non-selective agonist 120. The non-selective agonists agomelatine 2, and ramelteon 87 are drug candidates as antidepressive agent and for the treatment of insomnia and circadian rhythm disfunction, respectively.

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Design of subtype selective melatonin receptor agonists and antagonists

Cited by 56 publications

References 23 publications

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

MT₁ and MT₂ Melatonin Receptors: A Therapeutic Perspective

Recent Advances in Melatonin Receptor Ligands

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Design of subtype selective melatonin receptor agonists and antagonists

Cited by 56 publications

References 23 publications

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective

Recent Advances in Melatonin Receptor Ligands

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MT₁ and MT₂ Melatonin Receptors: A Therapeutic Perspective