Synthesis and structure–activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands

Leclerc, Véronique; Fourmaintraux, E.; Depreux, Patrick; Lesieur, D.; Morgan, Peter J.; Howell, H. E.; Renard, Pierre; Caignard, Daniel‐Henri; Pfeiffer, Bruno; Delagrange, Philippe; Guardiola‐Lemaître, B.; Andrieux, Jean

doi:10.1016/s0968-0896(98)00147-3

Cited by 33 publications

(29 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The relative position of the methoxy group and the N-acetylaminoethyl side chain seems to be an important determinant of affinity (Depreux et al, 1994;Langlois et al, 1995;Garratt et al, 1996). The indole ring is not essential for ligand binding because it can be replaced by various other aromatic systems such as naphthalene, benzofuran, benzothiophene, or benzocycloalkene rings (Depreux et al, 1994;Leclerc et al, 1998;Fukatsu et al, 2002). If methoxy and N-acylaminoethyl groups are positioned appropriately on these aromatic scaffolds, ligands with high affinity can result.…”

Section: B Structure-activity Relationshipsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

Dubocovich

Delagrange

Krause

et al. 2010

Pharmacological Reviews

Self Cite

535

510

View full text Add to dashboard Cite

Section: B Structure-activity Relationshipsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

Dubocovich

Delagrange

Krause

et al. 2010

Pharmacological Reviews

Self Cite

535

510

View full text Add to dashboard Cite

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: -7)mentioning

confidence: 99%

“…11) In addition, other groups such as amidotetralin, 21) methoxychroman, 22) amido indane, 23) benzofuran, 18,24) benzothiophene 18,24) and quinoline 25) can serve as a bioisostere of the indole nucleus of melatonin. Langlois et al reported that the addition of a 2-methoxy group (OMe) to compound 2 to form 3 results in an order of magnitude increase in receptor affinity over compound 2 (Fig.…”

Section: -7)mentioning

confidence: 99%

“…Currently, what we know is that the indole ring of melatonin is not crucial for melatonin receptor recognition. For instance, the naphthalene ring [11][12][13][14][15][16][17][18][19][20] can serve as a bioisostere of the indole nucleus of melatonin and analog 2 was reported to have equivalent affinity to melatonin for melatonin receptors in ovine pars tuberalis.11) In addition, other groups such as amidotetralin, 21) methoxychroman, 22) amido indane, 23) benzofuran, 18,24) benzothiophene 18,24) and quinoline 25) can serve as a bioisostere of the indole nucleus of melatonin. Langlois et al reported that the addition of a 2-methoxy group (OMe) to compound 2 to form 3 results in an order of magnitude increase in receptor affinity over compound 2 (Fig.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

Chu

Witt‐Enderby

Jones

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Melatonin is a hormone that is involved in a variety of physiological and pathological responses such as circadian rhythms, retinal physiology, seasonal breeding, cardiovascular regulation, anti-oxidative activity and oncogenesis. 1-7)Except anti-oxidative activity, melatonin may mediate its effect in vivo through melatonin receptors. Presently, two human melatonin receptor subtypes exist and are now defined as either the MT 1 8) (formerly known as the Mel 1a receptor) 9) and the MT 2 8) (formerly known as the Mel 1b receptor).10) The ability of melatonin or melatonin-like compounds to bind to and elicit physiological responses is dependent upon specific interactions between the ligand and receptor. The elucidation of the components of melatonergic ligands that are involved in high-affinity binding is becoming clearer. Currently, what we know is that the indole ring of melatonin is not crucial for melatonin receptor recognition. For instance, the naphthalene ring [11][12][13][14][15][16][17][18][19][20] can serve as a bioisostere of the indole nucleus of melatonin and analog 2 was reported to have equivalent affinity to melatonin for melatonin receptors in ovine pars tuberalis.11) In addition, other groups such as amidotetralin, 21) methoxychroman, 22) amido indane, 23) benzofuran, 18,24) benzothiophene 18,24) and quinoline 25) can serve as a bioisostere of the indole nucleus of melatonin. Langlois et al. reported that the addition of a 2-methoxy group (OMe) to compound 2 to form 3 results in an order of magnitude increase in receptor affinity over compound 2 (Fig. 1).12) It was postulated that the 2-OMe group binds to the accessory binding site of the receptor. Recently, we reported the synthesis and receptor binding studies of several analogs of 3 (general structure 4) with the substituents either hydrophilic or hydrophobic in nature with different sizes.16) Preliminary results show that analogs with smaller substituents in R, irrespective of their hydrophilic or hydrophobic nature, exhibit higher affinity for melatonin receptors when compared to those with larger substituents. We postulate that the close proximity of the amidoethyl side chain may be interfering with the conformation of the substituent on 2-position in 4 (Fig. 1). Thus, to determine the validity of this hypothesis, the amidoethyl group was transferred from C1 to C8 to eliminate the steric interference between the amidoethyl group and the substituent on 2-position in compound 4. The transfer should not affect the affinity of the ligands for the melatonin receptor as shown by Langlois et al. in which compound 5 (K i ϭ0.67 nM) has the same affinity for melatonin receptors in chicken brain when compared to compound 2 (K i ϭ0.54 nM) (Fig. 1). 12) After eliminating the steric interference of the amidoethyl side chain and the substituents on 2-position, we then synthesized compounds 6-10 with the substituents on 7-position of varying sizes. Results and ConclusionsChemistry The synthesis of compounds 6-10 is summarized in Fig. 2. Monobenzylation of 2,...

show abstract

Synthesis and structure–activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands

Cited by 33 publications

References 15 publications

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

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

Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

Contact Info

Product

Resources

About