Synthesis and in vitro binding of N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides for the peripheral benzodiazepine binding sites.
A series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides bearing the halogens iodine and bromine were synthesised and their binding affinity for the peripheral benzodiazepine binding sites (PBBS) in rat kidney mitochondrial membranes was evaluated using [(3)H]PK11195. Central benzodiazepine receptor (CBR) affinities were also evaluated in rat cortices using [(3)H]flumazenil to determine their selectivity for PBBS over CBR. The tested compounds had PBBS binding affinities (IC(50)) ranging from 7.86 to 618 nM, with all compounds showing high selectivity over the CBR (CBR IC(50) > 5000 nM). Among the 12 compounds tested, those with a diethylamide group were the most potent. The highest affinity iodinated PBBS ligand, N,N-diethyl-[5-chloro-2-(4-iodophenyl)indol-3-yl]glyoxylamide, was radiolabelled with iodine-123. This high affinity and selective radioligand may be useful for imaging neurodegeneration, inflammation and tumours using single photon emission computed tomography.
Department of Chemistry, University of Wollongong, NSW 2500, Wollongong, Australia.
Taryn P
TP
Homes
Filomena
F
Mattner
Paul A
PA
Keller
Andrew
A
Katsifis
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D005442:Flumazenil / Q000737:chemistry; D006038:Glyoxylates / Q000737:chemistry*; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry*; D007425:Intracellular Membranes / Q000187:drug effects; D007546:Isoquinolines / Q000737:chemistry; D007668:Kidney / Q000187:drug effects; D008024:Ligands; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000577:Amides; D006038:Glyoxylates; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; D011963:Receptors, GABA-A; D005442:Flumazenil; C037850:PK 11195