Alaproclate Explained

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]}

See also

• Femoxetine
• Indalpine
• Zimelidine

Notes and References

1. Alaproclate acts as a potent, reversible and noncompetitive antagonist of the NMDA receptor coupled ion flow . Wilkinson A, Courtney M, Westlind-Danielsson A, Hallnemo G, Akerman KE . The Journal of Pharmacology and Experimental Therapeutics . December 1994 . 271 . 3 . 1314–9 . 7996440 . subscription .
2. Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats . Nicholson KL, Balster RL . Psychopharmacology . November 2003 . 170 . 2 . 215–24 . 12851738 . 10.1007/s00213-003-1527-6. 30803162 .
3. Lindberg UH, Thorberg SO, Bengtsson S, Renyi AL, Ross SB, Ogren SO . 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 . May 1978 . 77901 . 10.1021/jm00203a008 .
4. 10.1002/jlcr.2580230905 . Synthesis of [¹⁴C]alaproclate . 1986 . Gawell L . Journal of Labelled Compounds and Radiopharmaceuticals . 23 . 9 . 947–949 .