The high affinity melatonin binding site probed with conformationally restricted ligands—I. Pharmacophore and minireceptor models

Structure-Affinity Relationships of Indole-Based Melatonin Analogs

“…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.…”

“…When the three-dimensional structure of the target molecule is unknown (as in the case of melatonin receptors), the development of highaffinity, conformationally constrained compounds represents an efficient approach to explore the requirements governing drug-receptor interactions. In parentheses, K i (nM ) values determined in quail brain membranes (27-37) [28], or taken from literature (38 [29], 39 [33], and 40 [34]). …”

“…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. To develop possible pharmacophore models of the MLT binding site, we subjected the binding results obtained for the most informative rigid compounds 28, 31, 33, 37 together with those collected from the literature for the conformationally constrained compounds (S)-38 [29], 39 [33], and 40 [34] (fig. 1) [28] to a computer molecular modeling study (DISCO module of Sybyl 6.3; Tripos Inc., St. Louis, Mo., USA).…”

Indole Melatonin Agonists and Antagonists Derived by Shifting the Melatonin Side Chain from the C-3 to the N-1 or to the C-2 Indole Position

“…In the resulting com-Biol Signals Recept 1999;8: [24][25][26][27][28][29][30][31] Tarzia/Diamantini/Spadoni pounds (2,(9)(10)(11)(12)(13)(14)(15), the distance between the methoxy group and the amido function is similar to that of MLT. Some of the structural changes reported for other series of melatonergic ligands were also applied to this series of compounds, including deletion of the methoxy substituent (compounds 5-8), its shift from the C-6 to the C-5 position (compound 3) and substitution at the C-2 indole position (compounds [13][14][15]. As in the natural indole series of melatonergic ligands, the presence and position of the methoxy group is critical to good affinity.…”

Synthesis and Pharmacological Analysis of High Affinity Melatonin Receptor Ligands.

“…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.…”