Recent developments in melatonin receptor ligands

Overproduction of reactive oxygen species results in oxidative stress that can cause fatal damage to vital cell structures. It is known that the use of antioxidants could be beneficial in the prevention or delay of numerous diseases associated with oxidative stress. Melatonin (MLT) is known as a powerful free-radical scavenger and antioxidant. It was found that indole ring of MLT can be employed by bioisosteric replacement by other aromatic rings. Quinoline derivatives constitute an important class of compounds for new drug development. Owing to quinoline and hydrazones appealing physiological properties and are mostly found in numerous biologically active compounds a series of quinoline-2-carbaldehyde hydrazone derivatives were synthesized as bioisosteric analogues of MLT, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Cytotoxicity potential of all compounds was investigated both by lactate dehydrogenase leakage assay and by MTT assay.

show abstract

“…These derivatives have structural resemblance to MLT, being derivatives of either substituted or bioisosteric moieties of the indole ring 10,11 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of antioxidant activity of new quinoline-2-carbaldehyde hydrazone derivatives: bioisosteric melatonin analogues

Püsküllü

Shirinzadeh

Nenni

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…These compounds possess a framework that is of importance in medicinal chemistry, as they can be ligands for a number of receptors for dopamine, [1] serotonin, [2] and melatonin. [3] The synthesis of arylmethylamines A can be realized from cyano derivatives of type B, which can be obtained through the addition of Me 3 SiCN to ketones C, [4] intramolecular epoxide ring-opening of compounds of type D, [5] Friedel-Craft-type reactions applied to compounds of type E [6] and F, [7] or intramolecular alkylation of α-bromoketones of type G. [5] In the particular case of α-halogenoketones, it is worth noting that the alkylation of nitriles is limited to α-bromoketones, as α-chloroketones did not lead to the cyclized products. Furthermore, the cyclized product was not formed when an ω-cyano epichlorhydrin was treated under basic conditions (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

First Intramolecular Alkylation of Nitriles with Primary and Secondary Alcohols Catalyzed by Iridium Complexes

et al. 2012

View full text Add to dashboard Cite

show abstract

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%

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

Recent developments in melatonin receptor ligands

Cited by 26 publications

References 34 publications

Synthesis and evaluation of antioxidant activity of new quinoline-2-carbaldehyde hydrazone derivatives: bioisosteric melatonin analogues

Synthesis and evaluation of antioxidant activity of new quinoline-2-carbaldehyde hydrazone derivatives: bioisosteric melatonin analogues

First Intramolecular Alkylation of Nitriles with Primary and Secondary Alcohols Catalyzed by Iridium Complexes

Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

Contact Info

Product

Resources

About