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Alpidem

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Alpidem
200px
Systematic (IUPAC) name
2-[3-chloro-8-(4-chlorophenyl)-1,7-diazabicyclo[4.3.0]nona-2,4,6,8-tetraen-9-yl]-N,N-dipropyl-acetamide
Clinical data
Oral
Pharmacokinetic data
Excretion Renal
Identifiers
82626-01-5 7pxY
None
PubChem CID 54897
ChemSpider 49570 7pxY
UNII I93SC245QZ 7pxY
KEGG D02833 7pxY
ChEMBL CHEMBL54349 7pxY
Chemical data
Formula C21H23Cl2N3O
404.332 g/mol
 14pxY (what is this?)  (verify)

Alpidem (Ananxyl) is an anxiolytic drug from the imidazopyridine family, related to the more well known sleeping medication zolpidem. Unlike zolpidem however, alpidem does not produce sedative effects at normal doses, and is instead used specifically for the treatment of anxiety.[1][2]

Alipidem was developed by Synthélabo (now part of Sanofi-Aventis). It was approved for marketing in France in 1991. Clinical trial to obtain US FDA approval were halted in 1992 and the drug never received FDA approval. It was withdrawn from the French market by 1994 and is not approved for marketing anywhere in the world.[3]

Alpidem has nanomolar binding affinity for both the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor (PBR) (translocator protein 18 kDa) (PBR (Ki ) 0.5-7 nM) and CBR (Ki ) 1-28 nM, respectively).[4] However the chemical structure of alpidem is not related to that of the benzodiazepines, and alpidem is thus sometimes referred to as a nonbenzodiazepine.[5]

Indications

Alpidem is not approved for any indication.

Use prior to removal from market

Alpidem was generally prescribed to patients with moderate to severe anxiety.[6] Most of these patients had exhibited either sensitivity or resistance to benzodiazepine therapy, and therefore switched to a non-benzodiazepine medication due to the reduced incidence of side effects relative to benzodiazepine drugs.[7][8] Alpidem produced little or no sedative or hypnotic action at normal doses but may have produced sedation when used at a high dose, and only had anticonvulsant actions at much higher doses than those used clinically for the treatment of anxiety.[9]

Dangers

In 1995, Alpidem was withdrawn from the market in most of the world following reports of severe liver damage.[10]

See also

References

  1. Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG. Pharmacological and behavioral profile of alpidem as an anxiolytic. Synthelabo Recherche, L.E.R.S., Bagneux, France. 1990 May;23 Suppl 3:108-13. PMID 1974069
  2. Sanger DJ, Zivkovic B. Discriminative stimulus effects of alpidem, a new imidazopyridine anxiolytic. Synthelabo Recherche, Bagneux, France. 1994 Jan;113(3-4):395-403. PMID 7862851
  3. WHO Drug Information Vol. 8, No. 2, 1994, page 64
  4. (a) Bourguignon, J. J. Endogenous and Synthetic Ligand of Mitochondrial Benzodiazepine Receptors: Structure-Affinity Relationships. In Peripheral Benzodiazepine Receptors; Giesen-Crouse, E., Ed.; Academic Press: London, 1993; pp 59-85. (b) Costa, E.; Romeo, E.; Auta, J.; Papadopoulos, V.; Kozikowski, A. P.; Guidotti, A. Is There a Pharmacology of Brain Steroidogenesis? In Neurosteroid and Brain Function, Fidia ResearchFundation Symposium Series; Costa, E., Paul, S. M., Eds.; Thieme Medical Publisher, Inc.: New York, 1991; pp 171-176. (c) Romeo, E.; Auta, J.; Kozikowski, A. P.; Ma, D.; Papadopoulos, V.; Puia, G.; Costa, E.; Guidotti, A. 2-Aryl-3-Indoleacetamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR). J. Pharmacol. Exp. Ther. 1992, 262, 971-978. (d) Kozikowski, A. P.; Ma, D.; Romeo, E.; Auta, J.; Papadopoulos, V.; Puia, G.; Costa, E.; Guidotti, A. Synthesis of (2-Arylindol-3-yl)acetamides as Probes of Mitochondrial Steroidogenesis - A New Mechanism for GABAA Receptor Modulation. Angew. Chem., Int. Ed. Engl. 1992, 31, 1060-1062.
  5. Diamond BI, Nguyen H, O'Neal E, Ochs R, Kaffeman M, Borison RL. A comparative study of alpidem, a nonbenzodiazepine, and lorazepam in patients with nonpsychotic anxiety. Psychopharmacology Bulletin. 1991;27(1):67-71.
  6. Kunovac JL, Stahl SM. Future directions in anxiolytic pharmacotherapy. Psychiatric Clinics of North America. 1995 Dec;18(4):895-909.
  7. Morton S, Lader M. Studies with alpidem in normal volunteers and anxious patients. Pharmacopsychiatry. 1990 May;23 Suppl 3:120-3.
  8. Frattola L, Garreau M, Piolti R, Bassi S, Albizzati MG, Borghi C, Morselli PL. Comparison of the efficacy, safety and withdrawal of alpidem and alprazolam in anxious patients. British Journal of Psychiatry. 1994 Jul;165(2):94-100.
  9. Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG. Pharmacological and behavioral profile of alpidem as an anxiolytic. Pharmacopsychiatry. 1990 May;23 Suppl 3:108-13.
  10. Berson A, et al. (2001) Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. J Pharmacol Exp Ther. 299(2):793-800.