title: 2-Aryl-3-indoleacetamides (FGIN-1): a new class of potent and specific ligands for the mitochondrial DBI receptor (MDR).
abstract: The 2 aryl-3-indoleacetamides (FGIN-1) are a new class of compounds that potently (nM) and selectively bind to glial mitochondrial diazepam binding inhibitor (DBI) receptors (MDR), previously called peripheral benzodiazepine receptors, and increase mitochondrial steroidogenesis. The high-affinity binding of FGIN-1 to MDR derivatives depends on the following chemical characteristics: 1) the dialkylation of the amide; 2) the chain length of this alkyl substitution; and 3) the halogenation of aryl groups appended to the indole nucleus. FGIN-1 derivatives do not bind to gamma-aminobutyric acid (GABAA), GABAB, glycine, glutamate, dopamine, serotonin, opiate, cholecystokinin, beta adrenergic, cannabinoid or sigma receptors. FGIN-1-27 [N, N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide] enters the brain, and for this reason, this FGIN-1 compound is potent and efficacious behaviorally. Like the neurosteroid 3 alpha-5 alpha tetrahydrodeoxycorticosterone (THDOC), FGIN-1-27 delays the onset of isoniazid-induced convulsions, but fails to delay the onset of bicuculline-induced convulsions. However, differently from THDOC, the FGIN-1-27 anticonvulsant action is blocked by the isoquinoline carboxamide PK 11195. In the elevated plus maze test, FGIN-1-27 inhibits neophobia manner that is antagonized by PK 11195 but not by flumazenil. Because FGIN-1-27 binds to MDR and does not bind to the GABAA receptors, it is inferred that FGIN-1-27 may act on GABAA receptors indirectly, presumably via a stimulation of neurosteroid synthesis and release from glial cells.
authors.affiliation: Fidia-Georgetown Institute for the Neurosciences, Washington, DC.
authors.forename: E
authors.initials: E
authors.lastname: Romeo
authors.forename: J
authors.initials: J
authors.lastname: Auta
authors.forename: A P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: D
authors.initials: D
authors.lastname: Ma
authors.forename: V
authors.initials: V
authors.lastname: Papadopoulos
authors.forename: G
authors.initials: G
authors.lastname: Puia
authors.forename: E
authors.initials: E
authors.lastname: Costa
authors.forename: A
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000633:toxicity; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D026261:Diazepam Binding Inhibitor; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007538:Isoniazid / Q000037:antagonists & inhibitors / Q000633:toxicity; D008024:Ligands; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism*; D011284:Pregnenolone / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced
chemical_list: D000081:Acetamides; D026261:Diazepam Binding Inhibitor; D007210:Indoleacetic Acids; D008024:Ligands; D009479:Neuropeptides; D011963:Receptors, GABA-A; D011284:Pregnenolone; D007538:Isoniazid; D001640:Bicuculline