Gérald Guillaumet

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.

Pyridine-Based Lanthanide Complexes: Towards Bimodal Agents Operating as Near Infrared Luminescent and MRI Reporters

We report two prototype Ln(3+) complexes that address requirements for both MRI and luminescence imaging and we demonstrate that the presence of two H(2)O molecules bound to the Ln(3+), beneficial for MRI applications of the Gd(3+) analogue, is not a major limitation for the development of NIR luminescent agents.

Aggressive behavior induced by the steroid sulfatase inhibitor COUMATE and by DHEAS in CBA/H mice

The steroid sulfatase enzyme (STS) regulates the formation of dehydroepiandrosterone (DHEA) from dehydroepiandrosterone-sulfate (DHEAS). DHEAS is a well-known negative allosteric modulator of the GABA(A) receptor-gated chloride channels. It is classified as an excitatory neurosteroid. The implication of GABA(A) receptor activity in aggressive behavior in rodents is well-documented. In addition a genetic correlation between STS level in the liver and aggressive behavior across 12 strains of mice suggest that STS activity could be involved in aggression in mice. We assessed herein whether COUMATE (an STS inhibitor) and DHEAS modulate aggression in CBA/H mice. We hypothesized that inhibiting STS activity in vivo followed by DHEAS injections which increase the level of sulfated steroid that cross the blood-brain barrier and then modulate neurotransmitter receptors could modify the attack behavior in mice. COUMATE (10 mg/kg) was administrated p.o. alone or in combination with the neurosteroid DHEAS (0-50 mg/kg) i.p. Animals were thereafter tested for aggression. A single dose of COUMATE significantly inhibited STS activity both in the brain (70.57%) and in the liver (87%) 24 h following administration. Behavioral tests showed that the inhibitor and DHEAS enhanced aggressive behavior when animals were simultaneously subjected to both molecules. These results confirm the correlation between aggressive behavior and STS concentration in mice. In addition, we confirm that the steroid metabolism can modulate the behavior in rodents.

Advances in direct C–H arylation of 5,5- 6,5- and 6,6-fused-heterocycles containing heteroatoms (N, O, S)

Direct arylation is a useful method for the preparation of (hetero)aryl–aryl systems by C–H bond cleavage. This procedure has several advantages such as the reduction of cost, time and waste. This report aims at reviewing the advances made in C–H arylation of 5,6, 6,6 and 5,5 fused-heterocyclic systems including: indole, azaindole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyrazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b][1,2,4,5]tetrazine, indolizine, pyrrolo[1,2-a]pyrazine, indazole, benzothiadiazole, benzotriazole, benzoxazole, benzofuran, benzothiophene, benzimidazole, benzothiazole, thieno[3,4-b]pyrazine, indolizine-2-carboxylate, thieno[3,4-b]pyrazine, quinoline and derivatives, chromanone, coumarin, quinoxaline, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, imidazo[2,1-b]thiazole, imidazo[1,2-b]pyrazole, thiazolo[3,2-b][1,2,4]triazoles and pyrrolo[3,2-b]pyrrole.

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.

A Novel, Unequivocal Synthesis of Polyethylene Glycols

Abstract Unequivocal synthesis of polyethyleneglycols is presented. The key step for this synthesis is the selective monobenzylation of oligoethyleneglycols by the phase transfer catalysis technique.

Solid support synthesis of 2,4-disubstituted thiazoles and aminothiazoles

Abstract 3-Iodobenzoic acid was loaded on Rink amide resin. Pd(0) coupling reaction with tributyl(1-ethoxyvinyl)tin followed by bromination using NBS gave an α-bromoketone bound to a solid support. Condensation of thioamide or thiourea, followed by TFA cleavage from the resin, gave 2,4-disubstituted thiazoles or 2-aminothiazoles, respectively. The primary amine of aminothiazole was treated with various acyl or sulfonyl chlorides to provide 2-substituted thiazole analogs.

Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release

Significance This paper describes the finding that mitochondria synthesize and release melatonin and have their selective G protein-coupled receptor (GPCR) in the outer membrane. We further demonstrate that mitochondrial melatonin type 1 receptors respond to melatonin by activating heterotrimeric G proteins located in the intermembrane space and inhibit stress-mediated cytochrome c release. This remarkable insight changes our classical understanding of biological GPCR function by showing that a cellular organelle both synthesizes and has a signaling receptor for a specific ligand. Implicit with our original work is the existence of an automitocrine signaling pathway by which melatonin prevents neurodegeneration associated with mitochondrial cytochrome c release and downstream caspase activation. G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT1), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT1 signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation. These findings coupled with our observation that mitochondrial MT1 overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, “automitocrine,” analogous to “autocrine” when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand–receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology.

Synthesis of 6,7,8,9-tetrahydropyrido[2,3-b]indolizine and 3,4-dihydro-2H-pyrido[2′,3′:4,5]pyrrolo[2,1-b][1,3]oxazine derivatives as new melatonin receptor ligands

Abstract The synthesis of new tricyclic azaindolic analogs of the hormone melatonin is described. Treatment of 1-(4-bromobutyl)pyrrolo[3,2- b ]pyridine derivative with tributyltin hydride and AIBN results in radical cyclisation to give the 6,7,8,9-tetrahydropyrido[2,3- b ]indolizine ring system. A new synthetic approach of pyridopyrrolo[2,1- b ][1,3]oxazine moiety is shown to be accomplished readily from 1-(3-bromopropyl)-2-oxopyrrolopyridine derivative with sodium hydride in N , N -dimethylformamide.

Design and synthesis of 2-phenylimidazo[1,2-a]pyridines as a novel class of melatonin receptor ligands.

A novel class of imidazo[1,2-a]pyridines as melatonin receptor ligands is designed and synthesized. The affinities of 3-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-N-methyl-propionamide 8, N-[2-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-ethyl]-acetamide 13 and N-(1-hydroxy-3-(5-methoxy-2-phenyl-1H-indol-3-yl)propan-2-yl)acetamide 18 are evaluated for binding on melatonin receptors. Compound 8 present good selectivity for MT(2) over MT(1) (MT(1)/MT(2) = 19) and compound 13 have good affinities for both MT(1) (Ki :28 nM) and MT(2) (Ki : 8 nM).