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

Abstract

Racemic N-(8-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)acetamide (compound 5) was previously identified as a novel selective MT(2) antagonist fulfilling the requirements of pharmacophore and 3D QSAR models. In this study the enantiomers of 5 were separated by medium-pressure liquid chromatography and behaved as the racemate. Compound 5 was modified at the acylaminomethyl side chain and at position C8. The resulting analogues generally behaved as melatonin receptor antagonists (GTPgammaS test) with a modest degree of selectivity (up to 10-fold) for the MT(2) receptor. Changes at the amide side chain led to a decrease in binding affinity, whereas 8-acetyl and 8-methyl derivatives 12 and 11, respectively, were as potent as the 8-methoxy parent compound 5. Docking experiments with an MT(2) receptor model suggested binding modes consistent with the observed SARs and with the lack of selectivity of the enantiomers of 5.

Description of the constitutive activity of cloned human melatonin receptors hMT1 and hMT2 and discovery of inverse agonists

“…We revisited part of our melatonin‐oriented chemical library and noticed a series of intriguing results that escaped our attention without the present context. Two heterotricyclic ligands recently reported with antagonistic activity, UCM 549 and UCM 724 [30], were re‐investigated and revealed, indeed, an inverse agonist effect at the melatonin receptors (Fig. 5).…”

“…GTPγS (Guanosine 5′‐[γ‐thio]triphosphate), Guanosine 5′‐diphosphate (GDP), Melatonin, PTX (Pertussis toxin, from Bordetella pertussis), GDP‐β‐S (guanosine 5′‐[β‐thio]‐diphosphate) were from Sigma‐Aldrich (Saint‐Quentin‐Fallavier, France). Compounds UCM 549 ( N‐ (8‐Methoxy‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐10‐yl‐methyl)acetamide) and UCM 724 ((8‐Methoxy‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐10‐yl‐methyl) urea) were a kind gift of Spadoni group [30]. All culture media were from Invitrogen (Carlsbad, CA, USA).…”

Structure-Based Virtual Screening of MT2 Melatonin Receptor: Influence of Template Choice and Structural Refinement

“…A subset of 21 “inactive” melatonin receptor ligands from the 12 chemical classes of the 29 active compounds was retrieved from the literature (Table S4, Supporting Information). ,− ,,,,− ,− Additional ligands were classified as inactive when their potency was at least 10-fold lower than that of active ligands from the same class. New screening runs were performed on the 50 compound set, and the number of false positives, i.e., the number of inactive compounds found in the top 29 positions, is reported in Table .…”

Direct, One-Pot Reductive Alkylation of Anilines with Functionalized Acetals Mediated by Triethylsilane and TFA. Straightforward Route for Unsymmetrically Substituted Ethylenediamine

“…In support of an ongoing medicinal chemistry research program in the melatonin field aimed at the discovery of new treatments for insomnia, there was a need for developing a safe and scalable synthetic process to supply a number of N -diarylaminoalkylamides 1 , a subclass of unsymmetrically substituted ethylenediamines (Figure ) . In particular, UCM765 ( 4a ) and UCM924 ( 4b ) were required in multigram quantities to fulfill preclinical development needs…”