Variations on a scaffold - Novel GABAA receptor modulators.

Allosteric ligands of GABAA receptors exist in many different chemotypes owing to their great usefulness as therapeutics, with benzodiazepines being among the best known examples. Many allosteric binding sites have been described, among them a site at the extracellular interface between the alpha principal face and the beta complementary face (α+/ß-). Pyrazoloquinolinones have been shown to bind at α+/ß-binding sites of GABAA receptors, exerting chiefly positive allosteric modulation at this location. In order to further explore molecular determinants of this type of allosteric modulation, we synthesized a library of ligands based on the PQ pharmacophore employing a ring-chain bioisosteric approach. In this study we analyzed the structure-activity-relationship (SAR) of these novel ligands based on an azo-biaryl structural motif in α1ß3 GABAA receptors, indicating interesting novel properties of the compound class.

Synthesis and characterization of bis- and tris-carbonyl Mn(I) and Re(I) PNP pincer complexes.

ABSTRACT: A series of neutral bis- and cationic tris-carbonyl complexes of the types cis-[M(κ3 P,N,P-PNP)(CO)2Y] and [M(κ3 P,N,P-PNP)(CO)3]+ was prepared by reacting [M(CO)5Y] (M = Mn, Re; Y = Cl or Br) with PNP pincer ligands derived from the 2,6-diaminopyridine, 2,6-dihydroxypyridine, and 2,6-lutidine scaffolds. With the most bulky ligand PNPNH-tBu, the cationic square-pyramidal 16e bis-carbonyl complex [Mn(PNPNH-tBu)(CO)2]+ was obtained. In contrast, in the case of rhenium, the 18e complex [Re(PNPNH-tBu)(CO)3]+ was formed. The dissociation of CO was studied by means of DFT calculation revealing in agreement with experimental findings that CO release from [M(κ3 P,N,P-PNP)(CO)3]+ is in general endergonic, while for [Mn(κ3 P,N,P-PNPNH-tBu)(CO)3]+, this process is thermodynamically favored. X-ray structures of representative complexes are provided.