André Mann

Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist.

Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers. In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction. Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction. Converging pharmacological,, human post-mortem and genetic studies implicate the dopamine D3 receptor in drug addiction. Here we have designed BP 897, the first D3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D3-receptor genes. BP 897 is a partial agonist in vitro and acts in vivo as either an agonist or an antagonist. We show that BP 897 inhibits cocaine-seeking behaviour that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects. Our data indicate that compounds like BP 897 could be used for reducing the drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli.

Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathophysiology of several mood disorders, including anxiety and depression. However, therapeutic compounds that interact with TrkB receptors have been difficult to develop. Using a combination of structure-based in silico screening and high-capacity functional assays in recombinant and neuronal cells, we identified a low-molecular weight TrkB ligand (ANA-12) that prevented activation of the receptor by BDNF with a high potency. ANA-12 showed direct and selective binding to TrkB and inhibited processes downstream of TrkB without altering TrkA and TrkC functions. KIRA-ELISA analysis demonstrated that systemic administration of ANA-12 to adult mice decreased TrkB activity in the brain without affecting neuronal survival. Mice administered ANA-12 demonstrated reduced anxiety- and depression-related behaviors on a variety of tests predictive of anxiolytic and antidepressant properties in humans. This study demonstrates that structure-based virtual screening strategy can be an efficient method for discovering potent TrkB-selective ligands that are active in vivo. We further propose that ANA-12 may be a valuable tool for studying BDNF/TrkB signaling and may constitute a lead compound for developing the next generation of therapeutic agents for the treatment of mood disorders.

Identification of two forms of glutamine synthetase in barley (Hordeum vulgare)

Abstract Two forms (designated GS I and GS II ) of glutamine synthetase (E.C.6.3.1.2) have been found in barley ( Hordeum vulgare ) which can be separated by ion exchange chromatography. Light grown shoots contain both GS I and GS II , roots, seeds and etiolated shoots exhibit only GS I activity. In light grown shoots GS II appears to be chloroplastic and GS I cytosolic. Sedimentation coefficients of both forms are similar (GS I , 14.04; GS II , 14.13 S 20 w) as are their Stokes radii (GS I , 6.13; GS II , 6.35 nm) and molecular weights (GS I 349,000; GS II 363,000 daltons). The pH optimum for GS II (pH 7.5) is somewhat more alkaline than that of GS I (pH 7.0). GS II is less stable than GS I ; in the absence of protective ligands it loses activity at 30°C and is inactivated by thiol reactive agents. GS I is stable at 30°C and its activity is unaffected by thiol reactive agents.

Acylthiourea, Acylurea, and Acylguanidine Derivatives with Potent Hedgehog Inhibiting Activity

The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC(50) values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.

The reactivity of N-tosylphenylaziridine versus N-tosylphenylazetidine in heterocyclization reactions

N-Tosylaziridine (1) and N-tosylazetidine (2) react as 1,3 and 1,4 masked dipoles with electron rich alkenes, respectively, either under kinetic or thermodynamic control. The reactivity of the new aza oxo [4.4.0] 9, a precursor of N-tosyliminium, was exploited for the preparation of stereodefined substituted piperidines.

Selective Removal of the Tert-Butoxycarbonyl Group from Secondary Amines: ZnBr2 as the Deprotecting Reagent

Abstract ZnBr2 in dichloromethane is a convenient reagent for mild and selective removal of the tert-butoxycarbonyl group from secondary amines.

Hydroformylation of Alkenylamines. Concise Approaches toward Piperidines, Quinolizidines, and Related Alkaloids

Linear hydroformylation of N-protected allyl- or homoallylamines (cyclohydrocarbonylation: CHC), followed by a reductive amination constitute the two key steps toward convenient routes to aza-heterocycles.

Hydroformylation of Homoallylic Azides: A Rapid Approach toward Alkaloids

Unprecedented hydroformylation of homoallylic azides combined with useful one-pot operations provides an expeditive access to alkaloids.

An approach to the synthesis of gelsemine: the intramolecular reaction of an allylsilane with an acyliminium ion for the synthesis of one of the quaternary centres

Abstract We describe an efficient synthesis (summarised in Schemes 8 and 10) of an advanced intermediate (34) suitable for the synthesis of gelsemine. The key steps in the synthesis are (i) the Diels-Alder reaction between 1-tetrahydropyranyloxycyclohexa-1,3-diene (10) and methyl β-nitroacrylate (11) giving an adduct (12), in which the chiral centre in the tetrahydropyranyl ring is produced substantially in only one sense, (ii) the rearrangement of a bicyclo [2.2.2] octane (23) into a bicyclo[ 3.2.1] octane (24), where control of which bridge migrates is achieved by a choice of the counterion in the Lewis acid, and (iii) the efficient formation of the quaternary centre by an intramolecular reaction between an allylsilane group and an acyliminium ion (33 → 34).

Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as Smoothened antagonists

The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N-(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N-(3-benzamidophenylcarbamoyl)-3,4,5-trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.