Tetrahydronaphthalenic derivatives as new agonist and antagonist ligands for melatonin receptors

Fourmaintraux, E.; Depreux, Patrick; Lesieur, D.; Guardiola‐Lemaître, B.; Bennejean, Caroline; Delagrange, P.; Howell, H. E.

doi:10.1016/s0968-0896(97)00175-2

Cited by 30 publications

(27 citation statements)

References 19 publications

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“…3B), clearly showing that CoASAT had travelled freely out of the cell, despite its size and relative hydrophilicity. This result is in agreement with previously published data showing that BAT can react with small quantities of free Coenzyme A (CoA-SH) 20 present in the reaction mixture to form CoASAT which, in turn, inhibits the hAANAT activity [12]. BAT incubation with the enzyme but without cosubstrate did not lead to CoASAT formation.…”

Section: Resultssupporting

confidence: 93%

See 1 more Smart Citation

New substrate analogues of human serotonin N‐acetyltransferase produce in situ specific and potent inhibitors

Ferry

Ubeaud

Mozo

et al. 2003

European Journal of Biochemistry

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Melatonin is synthesized by an enzymatic pathway, in which arylalkylamine (serotonin) N‐acetyltransferase catalyzes the rate‐limiting step. A previous study [Khalil, E.M., De Angelis, J., Ishii, M. & Cole, P.A. (1999) Proc. Natl Acad. Sci. USA96, 12418–12423] reported the discovery of bromoacetyltryptamine (BAT), a new type of inhibitor of this enzyme. This compound is the precursor of a potent bifunctional inhibitor (analogue of the transition state), capable of interfering with both the substrate and the cosubstrate binding sites. This inhibitor is biosynthesized by the enzyme itself in the presence of free coenzyme A. In the present report, we describe the potency of new N‐halogenoacetyl derivatives leading to a strong in situ inhibition of serotonin N‐acetyltransferase. The new concept behind the mechanism of action of these precursors was studied by following the biosynthesis of the inhibitor from tritiated‐BAT in a living cell. The fate of tritiated‐phenylethylamine (PEA), a natural substrate of the enzyme, in the presence or absence of [3H]BAT was also followed, leading to their incorporation into the reaction product or the inhibitor (N‐acetyl[3H]PEA and coenzyme A‐S[3H]acetyltryptamine, respectively). The biosynthesis of this bifunctional inhibitor derived from BAT was also followed by nuclear magnetic resonance during its catalytic production by the pure enzyme. In a similar manner we studied the production of another inhibitor generated from N‐[2‐(7‐hydroxynaphth‐1‐yl)ethyl]bromoacetamide. New derivatives were also screened for their capacity to inhibit a purified enzyme, in addition to enzyme overexpressed in a cellular model. Some of these compounds proved to be extremely potent, with IC50s of ≈ 30 nm. As these compounds, by definition, closely resemble the natural substrates of arylalkylamine N‐acetyltransferase, we also show that they are potent ligands at the melatonin receptors. Nevertheless, these inhibitors form a series of pharmacological tools that could be used to understand more closely the inhibition of pineal melatonin production in vivo.

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Section: Resultssupporting

confidence: 93%

“…Indeed, our data suggest that they are acetyl-CoA binding, as well as substratebinding site competitive inhibitors because they occupy the cosubstrate site. As these compounds are broad analogues of melatonin [16][17][18][19][20][21][22][23][24][25], we report their affinities for the MT 1 and/or MT 2 receptors.…”

mentioning

confidence: 99%

New substrate analogues of human serotonin N‐acetyltransferase produce in situ specific and potent inhibitors

Ferry

Ubeaud

Mozo

et al. 2003

European Journal of Biochemistry

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“…The affinity of compounds was determined by competition studies with 2-[ 125 l]-iodomelatonin, a specific radioligand for melatoninergic binding sites and the results, shown in Table 5, are expressed in terms of molar IC 50 . During previous research on melatonin analogs, 1 we demonstrated that replacement of indolic nucleus of melatonin with a tetrahydronaphthalenic one (compound 1) doesn't affect the affinity for the MT 2 receptor subtype and leads to a slight decrease in the affinity for the MT 1 receptor subtype. Consequently, the presence of this nucleus leads to an MT 2 selectivity 10 times as much as the melatonin one.…”

Section: Pharmacologymentioning

confidence: 96%

“…Therapeutic applications for melatonin ligands could be possible. 1,3,4 Some of us recently described the synthesis, the pharmacological and biochemical studies of tetrahydronaphthalenic derivatives 1 as potent and specific new agonist and antagonist melatoninergic ligands. To continue this work, we have further developed new compounds such as N-[2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]-acetamide 5 (Fig.…”

mentioning

confidence: 99%

Melatonin receptor agents: Synthesis, resolution by HPLC on polysaccharides chiral stationary phases, absolute configuration, and pharmacology of the enantiomers of (±)‐N‐[2‐(7‐fluoro‐1,2,3,4‐ tetrahydronaphthalen‐1‐yl)ethyl]acetamide

et al. 2001

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In order to obtain milligram amounts of the enantiomers of tetrahydronaphthalenic derivative 5 to be tested for binding to the melatonin sites, preparative HPLC employed a mobile phase consisting of n-hexane-alcohol and a silica-based cellulose tris-methylbenzoate (Chiralcel OJ) using isocratic conditions and multiple repetitive injections. The preparative separation was optimized by adjusting the sample size from a scale-up of the analytical method. The enantiomeric elution order was reversed by the change from the carbamate type phase (Chiralcel OD-H) to the benzoate type phase (Chiralcel OJ) in analytical mode. The optical rotation and the circular dichroism spectra of the single enantiomers were determined after separation. The absolute stereochemistry of the two enantiomers of (+/-)-N-[2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide 5 was established by X-ray crystallographic analysis. The purity obtained was sufficient for a first screen of their biochemical properties: the (-)-(S) enantiomer shows more affinity for melatonin receptors MT1, MT2 and is responsible of the selectivity towards MT2.

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“…Com- pound 67 (IC 50 ϭ 0.26 nM) exhibited only a 3-fold lower affinity than melatonin measured in radioligand binding studies at ovine pars tuberalis membranes [87]. Replacement of the methoxy group in 67 with an ethyl group, exemplified by compound 68 (Figure 7), generated ligands with considerably decreased binding affinity devoid of any agonist activity.…”

Section: Tetraline Analoguesmentioning

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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Tetrahydronaphthalenic derivatives as new agonist and antagonist ligands for melatonin receptors

Cited by 30 publications

References 19 publications

New substrate analogues of human serotonin N‐acetyltransferase produce in situ specific and potent inhibitors

New substrate analogues of human serotonin N‐acetyltransferase produce in situ specific and potent inhibitors

Melatonin receptor agents: Synthesis, resolution by HPLC on polysaccharides chiral stationary phases, absolute configuration, and pharmacology of the enantiomers of (±)‐N‐[2‐(7‐fluoro‐1,2,3,4‐ tetrahydronaphthalen‐1‐yl)ethyl]acetamide

Recent Advances in Melatonin Receptor Ligands

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