Medicinal chemistry of indolylglyoxylamide TSPO high affinity ligands with anxiolytic-like effects.
The mitochondrial translocator protein (TSPO) mediates the synthesis of neurosteroids in the CNS, which have been demonstrated to enhance the neurotransmitter GABA response, exhibiting related behavioural properties. Selective TSPO ligands are able to stimulate steroidogenesis with great efficacy, thus representing potential anxiolytic agents. This review describes the development of a class of high affinity ligands to TSPO, N,N-dialkylindol-3-ylglyoxylamides (IGA), from the initial stages of design to the pharmacological characterization of selected compounds for their anxiolytic activity. Affinity data and SARs of the new class of ligands are discussed; the potential applications of compounds characterized by the indolylglyoxylyl scaffold in diagnostic imaging are also pointed out.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. simorini@farm.unipi.it
Francesca
F
Simorini
Anna Maria
AM
Marini
Sabrina
S
Taliani
Concettina
C
La Motta
Silvia
S
Salerno
Isabella
I
Pugliesi
Federico
F
Da Settimo
D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D058785:GABA-A Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006038:Glyoxylates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D018377:Neurotransmitter Agents / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000577:Amides; D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006038:Glyoxylates; D007211:Indoles; D008024:Ligands; D018377:Neurotransmitter Agents; D021122:Protein Subunits; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C499229:TSPO protein, human