Alaproclate

Alaproclate
Clinical data
Routes of; administration	Oral
ATC code	N06AB07 (WHO) ;
Legal status
Legal status	In general: uncontrolled;
Identifiers
	IUPAC name 1-(4-Chlorophenyl)-2-methylpropan-2-yl 2-aminopropanoate;
CAS Number	60719-82-6 ; 60719-83-7 (hydrochloride);
PubChem CID	2081;
ChemSpider	1997 ;
UNII	C4R42570ZO;
KEGG	D02787 ;
ChEMBL	ChEMBL36591 ;
CompTox Dashboard (EPA)	DTXSID5045122 ;
Chemical and physical data
Formula	C13H18ClNO2
Molar mass	255.74 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Clc1ccc(cc1)CC(OC(=O)C(N)C)(C)C;
	InChI InChI=1S/C13H18ClNO2/c1-9(15)12(16)17-13(2,3)8-10-4-6-11(14)7-5-10/h4-7,9H,8,15H2,1-3H3 ; Key:FZSPJBYOKQPKCD-UHFFFAOYSA-N ;

Alaproclate (developmental code name GEA-654) is a drug that was being developed as an antidepressant by the Swedish pharmaceutical company Astra AB (now AstraZeneca) in the 1970s. It acts as a selective serotonin reuptake inhibitor (SSRI), and along with zimelidine and indalpine, was one of the first of its kind. Development was discontinued due to the observation of liver complications in rodent studies. In addition to its SSRI properties, alaproclate has been found to act as a non-competitive NMDA receptor antagonist, but does not have discriminative stimulus properties similar to phencyclidine.^[1]^[2]

Synthesis

The Grignard reagent, methylmagnesium iodide, reacts with methyl 4-chlorophenylacetate (1) to give the tertiary alcohol 1-(4-chlorophenyl)-2-methyl-2-propanol (2). Acylation with 2-bromopropionyl bromide (3) gives the ester (4) which, when treated with ammonia, yields alaproclate.^[3]^[4]

^ Wilkinson A, Courtney M, Westlind-Danielsson A, Hallnemo G, Akerman KE (December 1994). "Alaproclate acts as a potent, reversible and noncompetitive antagonist of the NMDA receptor coupled ion flow". The Journal of Pharmacology and Experimental Therapeutics. 271 (3): 1314–9. PMID 7996440.
^ Nicholson KL, Balster RL (November 2003). "Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats". Psychopharmacology. 170 (2): 215–24. doi:10.1007/s00213-003-1527-6. PMID 12851738. S2CID 30803162.
^ Lindberg UH, Thorberg SO, Bengtsson S, Renyi AL, Ross SB, Ogren SO (May 1978). "Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols". Journal of Medicinal Chemistry. 21 (5): 448–456. doi:10.1021/jm00203a008. PMID 77901.
^ Gawell L (1986). "Synthesis of [¹⁴C]alaproclate". Journal of Labelled Compounds and Radiopharmaceuticals. 23 (9): 947–949. doi:10.1002/jlcr.2580230905.