Synthesis and Preliminary Biological Evaluation of 2′‐Substituted 2‐(3′‐Carboxybicyclo[1.1.1]pentyl)glycine Derivatives as Group I Selective Metabotropic Glutamate Receptor Ligands

Abstract

The first series of 2'-substituted 2-(3'-carboxybicyclo[1.1.1]pentyl)glycine derivatives, (2R)- and (2S)-(2',2'-dichloro-3'-carboxybicyclo[1.1.1]pentyl)glycine (10) and (11), and 2-(2'-chloro-3'-carboxybicyclo[1.1.1]pentyl)glycine (12) were synthesized and evaluated as mGluR ligands. Compounds 11 and 12 were shown to be competitive group I mGluR antagonists. These results are also discussed in light of docking studies with both the active (closed) and inactive (open) conformations of mGluR1.

Cysteine-based chiral selectors for the ligand-exchange separation of amino acids☆

“…All the synthetized amino acidic compounds have been analyzed through chiral ligandexchange chromatography (CLEC) in order to assess the optical purity and, eventually, the enantiomeric excess. In some cases [11,14,15] we have also provided for the preparative separation of enantiomers through this technique: for example, 1-aminoindane-1,5-dicarboxylic acid (AIDA) enantiomers [14,15] have been successfully separated and tested for the first time.…”

“…Independent yet converging research efforts claim for a crucial involvement of Glu receptors in the mechanism of action of antidepressant [1], antipsychotic [2], antiparkinsonian [3,4] and nociceptive processing [5] drugs. Our continuing interest in this very challenging and promising field of research led us to develop potent and selective ligands for the various members of both ionotropic and metabotropic glutamate receptor families [6][7][8][9][10][11][12][13]. All the synthetized amino acidic compounds have been analyzed through chiral ligandexchange chromatography (CLEC) in order to assess the optical purity and, eventually, the enantiomeric excess.…”

S-Trityl-(R)-Cysteine, a Multipurpose Chiral Selector for Ligand-Exchange Liquid Chromatography Applications

“…During the past decade, we have performed several preparative RP-CLEC-based enantioisolations of chelating compounds endowed with one or more asymmetric carbon centers (Natalini et al, 2004a(Natalini et al, , 2008a(Natalini et al, , 2010bPellicciari et al, 2006).…”

“…C-CSPs (Natalini et al, 2008a) and recurring to chiral mobile phase additive (CMPA) to the eluent (Natalini et al, 2004a;Pellicciari et al, 2006). As the first effort in this direction, relying upon the CMPA system based on N,N-dimethyl-(S)-phenylalanine ((S)-DMP) units turned out to be highly advantageous for obtaining pure enantiomers of the glutamatergic pathway modulator 1-aminoindane-1,5-dicarboxylic acid (AIDA) (Natalini et al, 2004a).…”

Descriptive structure–separation relationship studies in chiral ligand‐exchange chromatography

“…Our continuing interest in CLEC methodology [15 -20], with explicit attention to the enantiodiscrimination of amino acids potentially useful as glutamatergic pathway modulators and particular consideration to the development of scale-up protocols [16,19,21], led us to apply for the first time a descriptive structure -separation relationship (DSSR) study with the intention to infer molecular properties of the analytes affecting the enantiodiscrimination in this chromatographic technique. In fact, this study consists of the development of a partition tree analysis based on a pool of molecular descriptors to explain the separation behavior of a selected set of analytes in the presence of a specific chiral discriminating agent.…”