Maria Elvira Tranquillini

2,4-Dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists: further characterization of 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester and structure-activity relationships.

Following the disclosure of 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester [3,5-dimethyl PPP] as a potent and selective mGluR1 non-competitive antagonist, we report here further in vivo characterization of this important tool and disclose the investigation of the C-5 position, which led to very potent compounds.

Glycine-site antagonists and stroke

The excitatory amino acid, (S)-glutamic acid, plays an important role in controlling many neuronal processes. Its action is mediated by two main groups of receptors: the ionotropic receptors (which include NMDA, AMPA and kainic acid subtypes) and the metabotropic receptors (mGluR(1-8)) mediating G-protein coupled responses. This review focuses on the strychnine insensitive glycine binding site located on the NMDA receptor channel, and on the possible use of selective antagonists for the treatment of stroke. Stroke is a devastating disease caused by a sudden vascular accident. Neurochemically, a massive release of glutamate occurs in neuronal tissue; this overactivates the NMDA receptor, leading to increased intracellular calcium influx, which causes neuronal cell death through necrosis. NMDA receptor activation strongly depends upon the presence of glycine as a co-agonist. Therefore, the administration of a glycine antagonist can block overactivation of NMDA receptors, thus preserving neurones from damage. The glycine antagonists currently identified can be divided into five main categories depending on their chemical structure: indoles, tetrahydroquinolines, benzoazepines, quinoxalinediones and pyrida-zinoquinolines.

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4-AMINO TRINEMS

Abstract This article deals with the study carried out on the synthesis of 4-amino substituted trinems 1 starting from the key-intermediate (3S, 4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1′R, 2′S, 3′R)-1′,2′-epoxycyclohex-3′-yl]azetidin-2-one 2 . In particular, epoxide opening with various amines and subsequent cyclization to the corresponding trinems were explored. Their synthesis and antimicrobial activity are reported.

Synthesis and evaluation of novel 1,5-Benzodiazepines as potent and selective CCK-B ligands. Effect of the substitution of the N-5 phenyl with alkyl groups

Abstract The synthesis and biological evaluation of both 3-ureido and 3-carbamate derivatives of 1,5-benzodiazepines bearing bulky alkyl substituents at N-1 and N-5 positions is reported. Their activity as CCK-B receptor antagonists is discussed and compared with the related N-5-phenyl derivatives.

Synthesis and structure-activity relationship of new 1,5-dialkyl-1,5-benzodiazepines as cholecystokinin-2 receptor antagonists.

This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.

2,4-Dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists: an exploration of the role of the pyrrolic scaffold.

Following the disclosure of 3-(1,2,2-trimethylpropyl) 4-[3,5-dimethyl-2-propyloxycarbonyl]pyrrolecarboxylate as a potent and selective mGluR1 non-competitive antagonist, the role and the importance of the pyrrole template were investigated. Different aromatic moieties were investigated as possible bio-isosteric replacement of the original scaffold and some of them were shown to be partially able to mimic the properties of the original pyrrole ring.

Diastereomeric separation of 1,5-benzodiazepines due to the presence of a chiral centre on the N-5 alkylic chain

The presence of a chain bearing a stereogenic centre at the N-5 position of 1-(1-adamantylmethyl)-3-arylureido-2,4-dioxo-1,5-benzodiazep ines induces optical resolution. The synthesis of these compounds and their potency as potential CCK-B receptor antagonists is discussed briefly here.

Synthesis and Evaluation of 1,5‐Benzodiazepines with Bridged Cycloalkyl Substituents at the N‐1 Position as Potent and Selective CCK‐B Ligands

The synthesis and biological evaluation of 3‐ureido and 3‐carbamate derivatives of 1,5‐benzodiazepines bearing bridged cycloalkyl substituents at N‐1 are reported. Their activity as CCK‐B receptor ligands is briefly discussed.