2-N-Acylaminoalkylindoles:  Design and Quantitative Structure−Activity Relationship Studies Leading to MT₂-Selective Melatonin Antagonists

Abstract

Several indole analogues of melatonin (MLT) were obtained by moving the MLT side chain from C(3) to C(2) of the indole ring. Binding and in vitro functional assays were performed on cloned human MT1 and MT2 receptors, stably transfected in NIH3T3 cells. Quantitative structure-activity relationship studies showed that 4-methoxy-2-(N-acylaminomethyl)indoles, with a benzyl group in position 1, were selective MT2 antagonists and, in particular, N-[(1-p-chlorobenzyl-4-methoxy-1H-indol-2-yl)methyl]propanamide (12) behaved as a pure antagonist at MT1 and MT2 receptors, with a 148-fold selectivity for MT2. We present a topographical model that suggests a lipophilic group, located out of the plane of the indole ring of MLT, as the key feature of the MT2 selective antagonists.

Synthesis, Enantiomeric Resolution, and Structure–Activity Relationship Study of a Series of 10,11‐Dihydro‐5H‐Dibenzo[a,d]cycloheptene MT2 Receptor Antagonists

“…However, the two cited solutions are qualitatively consistent with our previous knowledge and can help the interpretation of some observed SARs. Pose B is consistent with the antagonist behavior of this series and with the lack of influence of the substituent at position 8 on intrinsic activity; in fact, for many series of MLT receptor ligands, [14,31,32] intrinsic activity is strongly affected by the presence of substituents in a position corresponding to position 5 of the indole ring of MLT, and in particular it is enhanced by a methoxy group.…”

“…Analytical thin-layer chromatography (TLC) was carried out on Merck silica gel 60 F 254 plates. N-(10,11-dihydro-dibenzoA C H T U N G T R E N N U N G [b,f]thiepin-10-ylmethyl) acetamide (14) was purchased from Specs (The Netherlands). Triacetylcellulose (TAC), with a particle size of 15-25 mm, was purchased from Merck (Darmstadt, Germany).…”

“…[14] In particular, the presence of a lipophilic substituent in a position corresponding to positions 1-2 of the indole nucleus of MLT and non-coplanar with the indole ring was identified as a key element for MT 2 selectivity and decreased intrinsic activity. [14] The hypothesis was tested by statistical analysis, by means of a 3D QSAR investigation on structure-selectivity and structure-intrinsic activity with an extended set of MLT receptor ligands. [15] The information obtained from these analyses was applied to the design of a new series of MT 2 -selective ligands endowed with a novel tricyclic scaffold.…”

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…Other publications (Wallez et al, 2002;Audinot et al, 2003;Yous et al, 2003) reported selective MT 2 ligands with a benzyl substituent in the 2-position of benzofuran bioisosters (S 24014) or a phenyl substituent in the 3-position of tetrahydronaphthalenic (S 28407) or naphthalenic (S 24773) bioisosteres. Following the same rationale, Spadoni et al (2001) synthesized some melatonin derivatives, 2-acylaminoalkylindoles with a substitution by a benzyl in the 1-position (compound 12), that are selective for the MT 2 receptor type. Two other selective MT 2 ligands have been reported with rigidification of the side chain of melatonin with a piperidine amide chain (GR 128107) or piperazine amide chain (compound 13) (Dubocovich et al, 1997;Mattson et al, 2003).…”

Application of 3D-QSAR in the Rational Design of Receptor Ligands and Enzyme Inhibitors

“…In fact, a molecular-modeling study was undertaken to rationalize this result, based on the comparison of the structural features of 1 and of other reference antagonists, like luzindole, 4P-PDOT, and UCM454. Conformational analysis led to some important geometrical similarities between these structurally different compounds [26]. These antagonists are characterized by the presence of a substituent positioned out-of-the-plane of their core nucleus (i.e., the indole ring in luzindole or the tetralin scaffold in 4P-PDOT), and we hypothesized that this substituent conferred selectivity for the MT 2 receptor and led to a reduction of intrinsic activity.…”