Synthesis and structure-activity relationship studies in peripheral benzodiazepine receptor ligands related to alpidem.
The exploration of the structure-affinity relationships concerning a new class of peripheral benzodiazepine receptor (PBR) ligands related to alpidem has been pursued in order to evaluate the consistency of the structure-affinity relationships among different classes (and subclasses) of PBR ligands. The target amide derivatives were prepared following a previously published procedure based on the condensation of pyrrolo[3,4-b]quinoline derivatives 11a,b with glyoxylic acid mono-hydrate and the subsequent amidation of the acids obtained via mixed anhydride. On the other hand, the preparation of compound 9g lacking the pharmacophoric (delta1) carbonyl group involved: (a) the double sequential attack of the dimethylmethyleneammonium salt obtained from bis(dimethylamino)methane and acetyl chloride to pyrrolo[3,4-b]quinoline derivative 11b, (b) the quaternization of the obtained allylamine derivative 13 with methyl iodide, and (c) the palladium-catalyzed allylation of N-methyl-p-anisidine by quaternary allylammonium cation 14. The structure-affinity relationship trends observed in this subclass of tricyclic alpidem-related PBR ligands find correlations in other classes (or subclasses) of PBR ligands. This result supports the initial pharmacophoric hypothesis and suggests a common mode of interaction at the PBR binding site.
Cappelli
Andrea
A
Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it
Giuliani
Germano
G
Valenti
Salvatore
S
Anzini
Maurizio
M
Vomero
Salvatore
S
Giorgi
Gianluca
G
Sogliano
Cristiana
C
Maciocco
Elisabetta
E
Biggio
Giovanni
G
Concas
Alessandra
A
D000577:Amides / Q000737:chemistry; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000577:Amides; D002352:Carrier Proteins; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D011804:Quinolines; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C499229:TSPO protein, human; C069997:Tspo protein, rat; C052036:alpidem