Bivalent ligand approach on N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide: Synthesis, binding affinity and intrinsic activity for MT1 and MT2 melatonin receptors

Spadoni, Gilberto; Bedini, Annalida; Orlando, Pierfrancesco; Lucarini, Simone; Tarzia, Giorgio; Mor, Marco; Rivara, Silvia; Lucini, Valeria; Pannacci, Marilou; Scaglione, Francesco

doi:10.1016/j.bmc.2011.06.063

Cited by 14 publications

(8 citation statements)

References 31 publications

(28 reference statements)

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“…The first hMT 1 receptor‐selective agents were obtained by connecting two agomelatine units via their ether oxygen by (CH 2 ) 3 ‐ and (CH 2 ) 4 ‐linker to give S 26131 (antagonist) and S 26284 (partial agonist), both displaying ~100‐fold selectivity (Audinot et al, ; Descamps‐Francois et al, ). A similar approach led to the UCM 793 dimer with 100‐fold hMT 1 receptor selectivity and partial agonist activity (Spadoni et al, ). Monomeric ligands, such as CBOBNEA (Mesangeau et al, ), and AAE M PBP amine (Rivara et al, ) are partial agonists showing similar ~100‐fold selectivity for hMT 1 receptors.…”

Section: Introductionmentioning

confidence: 99%

“…Formation of receptor dimers offers the possibility to design dimeric ligands targeting receptor dimers. Several dimeric ligands with two identical pharmacophores have been synthesized for MT receptors and their binding properties have been determined (Audinot et al, ; Descamps‐Francois et al, ; Mesangeau et al, ; Spadoni et al, ; Journe et al, ). Binding of the two pharmacophores of these dimeric ligands to the two protomers of the same receptor dimer has been only shown in one study using a BRET approach (Journe et al, ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Update on melatonin receptors: IUPHAR Review 20

Jockers

Delagrange

Dubocovich

et al. 2016

British J Pharmacology

354

332

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Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist -MT 1 and MT 2 -encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Update on melatonin receptors: IUPHAR Review 20

Jockers

Delagrange

Dubocovich

et al. 2016

British J Pharmacology

354

332

View full text Add to dashboard Cite

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“…The most interesting compounds were those shown as 10a and 10b (Figure 3). 103 In particular, analogue 11b exhibited the highest MT 1 affinity (3.4 nM) and was 54 times more selective for MT 1 than for MT 2 receptors. Both compounds behave as partial MT 1 /MT 2 agonists, as assessed through [ 35 S]GTPγS binding analysis.…”

Section: Melatonergic Ligands In Developmentmentioning

confidence: 94%

Melatonergic drugs in development

Carocci¹,

Catalano²,

Sinicropi³

2014

CPAA

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Melatonin (N-acetyl-5-methoxytryptamine) is widely known as “the darkness hormone”. It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.

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“…20 The three series of dimeric melatonergic ligands published so far are compounds obtained by linking two agomelatine moieties by polymethylene spacers through their ether oxygens, 21 melatonin dimers obtained by connecting two molecules of melatonin through a C2-carboxyalkyl function, 22 and dimers of 3-methoxyaniline. 23 However, the spacer lengths applied (3-12 atoms) were too short for bridging dimeric receptors.…”

Section: Introductionmentioning

confidence: 99%

N1-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors

et al. 2014

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A novel series of dimeric melatonin analogues obtained by connecting two melatonin molecules through N1 with spacers of 15-24 atoms was synthesized and characterized in 2-[ 125 -I]-iodomelatonin binding and bioluminescence resonance energy transfer (BRET) experiments at MT 1 and MT 2 receptors. Compounds 4 (16 atoms spacer) and 13 (24 atoms spacer) are among the ligands inducing the maximal BRET at MT 2homodimers as well as at both types of MT 1 /MT 2 heterodimers. Notably, ligand-induced BRET changes observed for compounds linked through spacers of 22-24 atoms could be attributed to ligand-induced conformational changes between the two protomers of MT 1 and MT 2 homo-and heterodimers providing evidence for the binding of both pharmacophores of dimeric melatonin analogues to the two protomers of receptor dimers.

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Bivalent ligand approach on N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide: Synthesis, binding affinity and intrinsic activity for MT1 and MT2 melatonin receptors

Cited by 14 publications

References 31 publications

Update on melatonin receptors: IUPHAR Review 20

Update on melatonin receptors: IUPHAR Review 20

Melatonergic drugs in development

N1-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors

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