Benzo[b]thiophene derivatives. XVI. Sulfur isosteres of melatonin, bufotenine, 5-hydroxytryptophan, and related structures

Campaigne, E.; Dinner, A.

doi:10.1021/jm00300a042

Cited by 22 publications

(9 citation statements)

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“…40% yield by Meerwein arylation followed by reductive cyclisation, Fig. Sulfur was the earliest isosteric replacement for the nitrogen of indole [66,67], and was prepared from 3-bromomethyl-5-benzoylbenzo[b]thiophene (10), prepared by the route shown in Fig. 4) [65].…”

Section: Indole Benzo[b]thiophene Benzo[b]furan Benzimidazoles Inmentioning

confidence: 99%

Synthesis of Compounds as Melatonin Agonists and Antagonists

Garratt¹,

Tsotinis

2007

MRMC

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The functions of melatonin, the hormone of the pineal gland, are of considerable current interest. Synthetic melatonin analogues as agonists and antagonists have been explored in some detail and the molecule can be considered as consisting of an indole core, acting mainly as a spacer, and the 5-methoxyl and 3-amidoethyl side chains acting as the functional components, as originally proposed by Heward and Hadley. This review focuses on the synthetic routes to these melatonin analogues, first of the core, then of the substituents that have been attached to the core, and finally those compounds with restricted conformations and those that are chiral. The importance of the various factors involved in the activity of the compounds as agonist or antagonists is indicated, as is the difference in activity of enantiomers.

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Section: Indole Benzo[b]thiophene Benzo[b]furan Benzimidazoles Inmentioning

confidence: 99%

Synthesis of Compounds as Melatonin Agonists and Antagonists

Garratt¹,

Tsotinis

2007

MRMC

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“…12 -15 To obtain the amine hydrochloride 7i, we used the general synthetic approach described by Campaigne (Scheme 1). 14 Condensation of 4-ethylthiophenol with ethyl-4-chloroacetoacetate in pyridine gave the ketoester 2, which was cyclized with polyphosphoric acid to give compound 3. Hydrolysis of the ester function with sodium hydroxide afforded the corresponding acid 4.…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis and In Vitro Evaluation of Novel Derivatives as Serotonin N -Acetyltransferase Inhibitors

Beaurain

Mésangeau

Chavatte

et al. 2002

Journal of Enzyme Inhibition and Medicinal Chemistry

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Serotonin N-acetyltransferase (arylalkylamine N-acetyl-transferase, AANAT) is an enzyme that catalyses the first rate limiting step in the biosynthesis of melatonin (5-methoxy-N-acetyltryptamine). Different physiopathological disorders in human may be due to abnormal secretion of melatonin leading to an inappropriate exposure of melatonin receptors to melatonin. For that reason, we have designed, synthesized and evaluated as inhibitors of human serotonin N-acetyltransferase, a series of compounds that were able to react with coenzyme A to give a bisubstrate analog inhibitor. Compound 12d was found to be a potent AANAT inhibitor (IC50 = 0.18 microM).

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“…The methoxy group highly enhances binding affinity by forming a hydrogen bond with His211 in the putative transmembrane domain 5 (TM5) of the receptor [11,12], and potent heterocyclic bioisosters of indoles [13][14][15][16][17][18], and our earlier findings using substituted phenylalkylamides (e.g. 2 and 3) [11].…”

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confidence: 99%

“…The proton donor NH indole is not essential for binding, as has been demonstrated by various A number of structure-activity relationships have been identified [ proposed molecular models of the melatonin binding site: the key elements for high binding affinity are the presence and the relative spatial position of the methoxy group and the N-alkanamido side chain linked to an appropriate spacer [9,10]. The methoxy group highly enhances binding affinity by forming a hydrogen bond with His211 in the putative transmembrane domain 5 (TM5) of the receptor [11,12], and potent heterocyclic bioisosters of indoles [13][14][15][16][17][18], and our earlier findings using substituted phenylalkylamides (e.g. These results prompted us to determine whether the presence of small and larger carbocycles in the -position of the alkanamido side chain of simple 3-methoxy benzenes has the same effect on melatoninergic potency as in aromatic heterocyclic "frameworks".…”

mentioning

confidence: 99%

An Efficient Synthesis of Simple β,β -Cyclobisalkylated Melatoninergic Phenylalkylamides

Tsotinis¹,

Vlachou²,

Papahatjis³

et al. 2007

LOC

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Treatment of the commercially available 3-methoxyphenylacetonitrile (6) with sodium bis (trimethylsilyl)amide and subsequent cyclobisalkylation with , -dibromo or dichloroalkanes in THF at 0 o C produces adducts 7a-d , which serve as precursors to the new conformationally constrained phenylalkylamides 5a-h . Compounds 5a-f are melatonin receptor agonists in the Xenopus laevis melanophore assay and their potency depends on both the size of the R group and the size and shape of the -substituent. The fact that the cyclohexano-substituted analogs 5g and 5h are, regardless of the size of the R group, melatonin receptor antagonists, implies that the nature of the -substituent constitutes a functional probe in the receptor's dynamic agonist-antagonist conformational equilibrium.Keywords: N-acyl 1-(3-methoxyphenyl)cycloalkanomethanamines, design, synthesis, melatoninergic activity.Melatonin (N-acetyl-5-methoxytryptamine, 1), the hormone secreted by the pineal gland, is a major component in the control of circadian rhythms in humans and other animals [1,2]. Since the identification of three distinct melatonin receptor subtypes [3][4][5][6][7] there have been numerous studies in an attempt to understand how melatonin interacts with its receptors. the side chain by acting as both hydrogen bond donor and acceptor, provided that it is capable of spending ample time in the preferred binding conformation [11]. One way of accomplishing this is by introducing -substituents in the 3-N-acetyl ethylamine side chain of melatonin, forcing it to orientate orthogonally to the plane of the indole ring. As a result the population of the preferred conformation is sufficiently increased [8]. The proton donor NH indole is not essential for binding, as has been demonstrated by various A number of structure-activity relationships have been identified [8] and recently we and other researchers have N H NHCOCH 3 H 3 CO N H NHCOCH 3 O NHCOR 1: melatonin 3: R=n-C 3 H 7 (pEC 50 =8.32 [11]) 4: luzindole 2: R=C 2 H 5 (pEC 50 =8.28 [11])proposed molecular models of the melatonin binding site: the key elements for high binding affinity are the presence and the relative spatial position of the methoxy group and the N-alkanamido side chain linked to an appropriate spacer [9,10]. The methoxy group highly enhances binding affinity by forming a hydrogen bond with His211 in the putative transmembrane domain 5 (TM5) of the receptor [11,12], and potent heterocyclic bioisosters of indoles [13][14][15][16][17][18], and our earlier findings using substituted phenylalkylamides (e.g. 2 and 3) [11].These results prompted us to determine whether the presence of small and larger carbocycles in the -position of the alkanamido side chain of simple 3-methoxy benzenes has the same effect on melatoninergic potency as in aromatic heterocyclic "frameworks". In the skeleton of the new molecules (5a-h, Scheme 1) the methoxy group present in 2 and 3 has been retained and in their side chain various cycloalkanes have been incorporated.

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Benzo[b]thiophene derivatives. XVI. Sulfur isosteres of melatonin, bufotenine, 5-hydroxytryptophan, and related structures

Cited by 22 publications

References 0 publications

Synthesis of Compounds as Melatonin Agonists and Antagonists

Synthesis of Compounds as Melatonin Agonists and Antagonists

Design, Synthesis and In Vitro Evaluation of Novel Derivatives as Serotonin N -Acetyltransferase Inhibitors

An Efficient Synthesis of Simple β,β -Cyclobisalkylated Melatoninergic Phenylalkylamides

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Benzo[b]thiophene derivatives. XVI. Sulfur isosteres of melatonin, bufotenine, 5-hydroxytryptophan, and related structures

Cited by 22 publications

References 0 publications

Synthesis of Compounds as Melatonin Agonists and Antagonists

Synthesis of Compounds as Melatonin Agonists and Antagonists

Design, Synthesis and In Vitro Evaluation of Novel Derivatives as Serotonin N -Acetyltransferase Inhibitors

An Efficient Synthesis of Simple &#946;,&#946; -Cyclobisalkylated Melatoninergic Phenylalkylamides

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An Efficient Synthesis of Simple β,β -Cyclobisalkylated Melatoninergic Phenylalkylamides