1-(2-Alkanamidoethyl)-6-methoxyindole Derivatives:  A New Class of Potent Indole Melatonin Analogues

Abstract

A new series of indole melatonin analogues, bearing the amido ethyl side chain attached at the N-1 position of the indole nucleus, were synthesized and tested for their affinity for the melatonin receptor isolated from quail optic tecta in a series of in vitro ligand-binding experiments using 2-[125I]iodomelatonin as the labeled ligand. The biological activity was evaluated using two models: effects on the forskolin-stimulated cAMP accumulation in explants from quail optic tecta and evaluation of the GTP gamma S index derived from competition experiments performed in the absence or presence of GTP gamma S. Compounds 2a and 2k-n, obtained by shifting the methoxy group and the ethylamido side chain from the C-5 and C-3 positions of melatonin to the C-6 and N-1 positions of the indole nucleus, exhibited an affinity similar to that of melatonin itself, as well as full agonist activity. Optimization of the C-2 substituent by introducing Br, phenyl, or COOCH3 (2b-d) resulted in a significantly enhanced affinity (in the picomolar range) and improved agonist biological activity. Compounds lacking the methoxy group and bearing an N-alicyclic group (2h-j) behaved as partial agonists or antagonists.

Structure-Affinity Relationships of Indole-Based Melatonin Analogs

“…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.…”

“…The acyl group influences the affinity and the nature of the compounds to behave as agonists, partial agonists or antagonists. N-acetylated compounds were full agonists (22)(23)(24) or partial agonists (19)(20)(21), whereas the N-cyclobutanecarbonylamino derivatives (25,26) …”

“…The relative intrinsic activity values were obtained by dividing the maximal G-protein activation of a test compound by that of MLT. Prior to the cloning of human melatonin receptors, the efficacy was evaluated according to the following methods: (a) effects on forskolin-stimulated cAMP accumulation; (b) effects of coincubation with GTPÁS on the IC 50 values (GTPÁS index) [26].…”

Conformational changes in matrix-isolated 6-methoxyindole: Effects of the thermal and infrared light excitations

“…[23][24][25] From a wider perspective, the results obtained in this work provide basic knowledge that can be used to understand local conformational features in many relevant methoxyindole-containing naturally occurring and synthetic biomolecules. [26][27][28][29][30] Also, the possibility of controlling the conformational distribution of 6MOI in matrices opens a window for exploiting its conformer-specific reactivity in condensed media (as opposite to the gas phase). In addition, this work also demonstrates in a very clear way that exposition of a conformationally flexible sample to the broadband FIG.…”

MT2 selective melatonin receptor antagonists: design and structure-activity relationships

“…We synthesized different series of melatonin analogues, obtaining very potent derivatives, such as 2-bromomelatonin. 8,9,10,11 Starting from a series of conformationally constrained compounds, we proposed a pharmacophore model for agonists and a bioactive conformation for the natural ligand. 12 A 3D-QSAR CoMFA analysis allowed the rationalization of the structure-activity relationships for more than one hundred agonists.…”