Structural requirements at the melatonin receptor

Sugden, David; Chong, Nelson W.; Lewis, David F.

doi:10.1111/j.1476-5381.1995.tb17184.x

Cited by 64 publications

(50 citation statements)

References 39 publications

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“…Previous data indicated that the 5-methoxy group is a major determinant in the attachment of MLT to its receptors [18] and there is evidence that it can influence the intrinsic activity, even if there are a number of examples of agonists that do not have the methoxy group [22][23][24][25][26]. A more extensive investigation of the importance of the methoxy substituent for biological activity and selectivity toward human mt 1 and MT 2 receptors was investigated by deleting this group or by shifting it from C-5 to the other indole positions.…”

Section: Substituent Modification On the Indole Nucleusmentioning

confidence: 99%

“…A number of molecular modeling studies of the MLT receptors have been reported [18,[29][30][31][32]. The level of sophistication of these models varies considerably as do the number and diversity of compounds on which they are based and on the building approach.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…The earliest SAR studies on indole derivatives of MLT demonstrated that both the 5-methoxy and N-acylamino groups are important for binding to and activating the MLT receptor [18]. The indole nucleus serves as a spacer between these two groups and can be replaced by other bioisosteric nuclei.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Affinity Relationships of Indole-Based Melatonin Analogs

1999

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This paper reviews our progress made in characterizing structure-affinity relationships of indole-based melatonin analogs. Evidence is presented suggesting a preferred folded conformation for the amido side chain, almost orthogonal to the plane of indole. A 3D-QSAR comparative molecular field analysis (CoMFA) model, accounting for the observed differences in binding affinity within different classes of melatonergic ligands, and capable of quantitatively predicting the binding affinity of new compounds, is also reported.

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Section: Substituent Modification On the Indole Nucleusmentioning

confidence: 99%

Section: Molecular Modelingmentioning

confidence: 99%

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Structure-Affinity Relationships of Indole-Based Melatonin Analogs

1999

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“…This product (I.a) also features in some QSAR expressions, such as those for melatonin analogues [44], thus indicating that dispersion forces could be involved in melatonin receptor binding. Furthermore, it is possible to make a reasonable estimate of the binding affinity between melatonin and its receptor based on the Williams et al [45] expression for the various components likely to be involved, with hydrogen bonding (see Table 3 for some typical values) making a significant contribution [46]. In contrast, a derivation for the binding energy of camphor to cytochrome P450 cam indicates that hydrophobic forces (desolvation) make the largest contribution [34].…”

Section: Appendix a Derivation Of Solvation And Desolvation Energiesmentioning

confidence: 99%

Molecular Binding Interactions: Their Estimation and Rationalization in QSARs in Terms of Theoretically Derived Parameters

Lewis

Broughton

2002

The Scientific World JOURNAL

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An extensive survey of molecular binding interactions and parameters used in QSARs is reported, which includes consideration of lipophilicity and the derivation of Linear Free Energy Relationships associated with drug-receptor binding, together with an overview of the various contributions to binding energy. The lipophilic parameter, log P, and its relevance to desolvation energy is outlined and explanation of the parameters derived from electronic structure calculation is provided, leading into a summary of molecular dynamics simulations. KEY WORDS: drug-receptor binding interactions, quantitative structure-activity relationships (QSARs)

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“…16) It has been stated that the 5-methoxy group in melatonin is involved in critical hydrogen bonding to the receptor recognition site. 28) If it is assumed that the methoxy group in compound 4 mimics the 5-methoxy group of melatonin, then transferring the amidoethyl group from C1 to C8 eliminated the steric interference between the amidoethyl group and the 2 substituent in compound 4 and resulted in an increase in binding affinity to both MT 1 and MT 2 receptors.…”

Section: Results and Conclusionmentioning

confidence: 99%

Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

Chu

Witt‐Enderby

Jones

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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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,...

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Structural requirements at the melatonin receptor

Cited by 64 publications

References 39 publications

Structure-Affinity Relationships of Indole-Based Melatonin Analogs

Structure-Affinity Relationships of Indole-Based Melatonin Analogs

Molecular Binding Interactions: Their Estimation and Rationalization in QSARs in Terms of Theoretically Derived Parameters

Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

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