Pierre Renard

Agomelatine, the first melatonergic antidepressant: discovery, characterization and development

Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.

New selective ligands of human cloned melatonin MT1 and MT2 receptors

Melatonin has a key role in the circadian rhythm relay to periphery organs. Melatonin exerts its multiple roles mainly through two seven transmembrane domain, G-coupled receptors, namely MT1 or MT2 receptors. A pharmacological characterization of these human cloned melatonin hMT1 and hMT2 receptors stably expressed in HEK-293 or CHO cells is presented using a 2-[125I]-iodo-melatonin binding assay and a [35S]-GTPγS functional assay. Both reference compounds and new chemically diverse ligands were evaluated. Binding affinities at each receptor were found to be comparable on either HEK-293 or CHO cell membranes. Novel non-selective or selective hMT1 and hMT2 ligands are described. The [35S]-GTPγS functional assay was used to define the functional activity of these compounds which included partial, full agonist and/or antagonist activity. None of the compounds acted as an inverse agonist. We report new types of selective antagonists, such as S 25567 and S 26131 for MT1 and S 24601 for MT2. These studies brought other new molecular tools such as the selective MT1 agonist, S 24268, as well as the non-selective antagonist, S 22153. Finally, we also discovered S 25150, the most potent melatonin receptor agonist, so far reported in the literature.

Melatonin analogues as agonists and antagonists in the circadian system and other brain areas

We studied the effects of drugs related to melatonin on neuronal firing activity in the suprachiasmatic nucleus, intergeniculate leaflet and other brain areas in urethane-anesthetized Syrian hamsters. We tested melatonin and two naphthalenic derivatives of melatonin, a putative agonist (S20098: N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide), and a putative antagonist (S20928: N-[2-(1-naphthyl)ethyl]cyclobutyl carboxamide). Both melatonin and S20098 given intraperitoneally (i.p.) were able to suppress firing rates of cells in a similar dose-dependent manner, but the effects of S20098 were longer lasting. Iontophoresis of melatonin dose dependently depressed spontaneous and light-evoked activity of cells in the suprachiasmatic nucleus and intergeniculate leaflet, while iontophoresis of S20098 was relatively ineffective, probably because it is a poorly charged compound. S20928 (2.0-10 mg/kg, i.p.) alone decreased firing rates of light-sensitive cells by 25-50% for 5-30 min in the suprachiasmatic nucleus and intergeniculate leaflet; however, low doses (< 2.0 mg/kg) of S20928 partially blocked the effects of melatonin agonists on most cells. The non-selective serotonin antagonist metergoline did not block the effects of either melatonin agonist. Both melatonin agonists and antagonists were less effective when applied to cells in the hippocampus and dorsal lateral geniculate nucleus. These results indicate that S20098 is an agonist acting probably on melatonin receptors in the Syrian hamster brain. S20928 may have mixed agonist/antagonist properties, but at low doses appears to function as an antagonist at melatonin receptors in the suprachiasmatic nucleus and intergeniculate leaflet.

Structure–activity relationships and structural conformation of a novel urotensin II-related peptide

Urotensin II (UII) has been described as the most potent vasoconstrictor peptide and recognized as the endogenous ligand of the orphan G protein-coupled receptor GPR14. Recently, a UII-related peptide (URP) has been isolated from the rat brain and its sequence has been established as H-Ala-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH. In order to study the structure-function relationships of URP, we have synthesized a series of URP analogs and measured their binding affinity on hGPR14-transfected cells and their contractile activity in a rat aortic ring bioassay. Alanine substitution of each residue of URP significantly reduced the binding affinity and the contractile activity of the peptides, except for the Ala8-substituted analog that retained biological activity. Most importantly, D-scan of URP revealed that [D-Trp4]URP abrogated and [D-Tyr6]URP partially suppressed the UII-evoked contractile response. [Orn5]URP, which had very low agonistic efficacy, was the most potent antagonist in this series. The solution structure of URP has been determined by 1H NMR spectroscopy and molecular dynamics. URP exhibited a single conformation characterized by an inverse gamma-turn comprising residues Trp-Lys-Tyr which plays a crucial role in the biological activity of URP. These pharmacological and structural data should prove useful for the rational design of non-peptide ligands as potential GPR14 agonists and antagonists.

A convenient extension of the Wessely-Moser rearrangement for the synthesis of substituted alkylaminoflavones as neuroprotective agents in vitro.

A series of 8-alkylamino-5,7-dihydroxyflavones was prepared from chrysine via a seven step sequence. The synthesis of their 6-alkylamino isomers could be subsequently accomplished through a convenient extension of the Wessely-Moser rearrangement. These compounds were found to be efficient neuroprotective agents in vitro.

Novel antitumor artemisinin derivatives targeting G1 phase of the cell cycle

Modification of artemisinin structure led us to the discovery of a novel class of antitumor compounds. These artemisinin derivatives containing cyano and aryl groups showed potent antiproliferative effect in vitro against P388 and A549 cells. This activity was reflected in P388 murine leukemia by an accumulation of cells in G1 phase, and induction of apoptosis.

Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction

The sequence of human urotensin II (UII) has been recently established as H-Glu-Thr-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH, and it has been reported that UII is the most potent mammalian vasoconstrictor peptide identified so far. A series of UII analogues was synthesized, and the contractile activity of each compound was studied in vitro using de-endothelialised rat aortic rings. Replacement of each amino acid by an l-alanine or by a d-isomer showed that the N- and C-terminal residues flanking the cyclic region of the amidated peptide were relatively tolerant to substitution. Conversely, replacement of any residue of the cyclic region significantly reduced the contractile activity of the molecule. The octapeptide UII(4–11) was 4 times more potent than UII, indicating that the C-terminal region of the molecule possesses full biological activity. Alanine or d-isomer substitutions in UII(4–11) or in UII(4–11)-NH2, respectively, showed a good correlation with the results obtained for UII-NH2. Disulfide bridge disruption or replacement of the cysteine residues by their d-enantiomers markedly reduced the vasoconstrictor effect of UII and its analogues. In contrast, acetylation of the N-terminal residue of UII and UII-NH2 enhanced the potency of the peptide. Finally, monoiodination of the Tyr6 residue in UII(4–11) increased by 5 fold the potency of the peptide in the aortic ring bioassay. This structure–activity relationship study should provide useful information for the rational design of selective and potent UII receptor agonists and antagonists.

Synthesis of new pyrrolo(1,2-a)quinoxalines: potential non-peptide glucagon receptor antagonists

Synthesis of new pyrrolo[1,2-a]quinoxaline derivatives was achieved starting from various nitroanilines or orthophenylenediamines. Their affinity towards glucagon receptors was evaluated

Expeditious synthesis and cytotoxic activity of new cyanoindolo[3,2-c]quinolines and benzimidazo[1,2-c]quinazolines

Novel 6-cyanoindolo[3,2-c]quinoline and 6-cyanobenzimidazo[1,2-c]quinazoline derivatives have been synthesised by treatment of the appropriate aromatic amines with 4.5-dichloro-1,2,3-dithiazolium chloride 1 (Appel salt). The cytotoxicity and the effect of these compounds on cellular growth were measured.

Synthesis of isoquinolines and tetrahydroisoquinolines as potential antitumour agents

Abstract The isoquinoline 17 and the tetrahydroisoquinoline 16 were synthesized from 2,3-dihydro-1,4-benzodioxin (1) by different synthetic strategies. Preparation of arylethylamines and their cyclization in Bischler–Napieralski conditions have been studied. Another approach to isoquinolines was based on the amination of the ketone 13 followed by cyclization in acidic media. The route via the amide 15 was found to be more successful with respect to both yield and ease of reaction.