Structural Biochemistry/Paxin

Introduction

Miltown, generically known as Meprobamate, is a sedative drug that is used to treat anxiety and short-term manage insomnia. It is a carbamate derivative that was one used as a minor tranquilizer.

History

Meprobamate was first synthesized by Bernard John Ludwig, PhD, and Frank Milan Berger, MD, at Carter Products in May 1950. Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining notoriety for its seemingly miraculous effects.

In the mid-1940s, Dr. Berger was working in a laboratory of a British drug company, looking for a preservative for penicillin, when he noticed that a compound called mephenesin had a sedative effect in small laboratory animals. However, there were three major drawbacks to the use of mephenesin as a tranquilizer: a very short duration of action, greater effect on the spinal cord than on the brain, and a weak activity. After moving to Wallace Laboratories in New Jersey, Dr. Berger and a chemist, Dr. Bernard Ludwig, synthesized a chemically-related tranquilizing compound, meprobamate, that was able to overcome these three drawbacks and began marketing this new drug.

Pharmacology

Although it is marked as being safer, Meprobamate share many of the pharmacological effects and dangers of barbiturates.

The mechanism that Meprobamate undergoes is unknown, although studies show that it affects multiple sites of the central nervous system, including the limbic and thalamus systems. Meprobamate binds to GABA_A receptors, interrupting neural communication in the reticular formation and spinal chord, causing sedation and altered perception of pain.

Toxicity

If overdosed, symptoms include coma, drowsiness, loss of muscle control, impaired breathing, sluggishness, and unresponsiveness. Death has been reported with the ingestion of as little as 12 grams and survival with as much as 40 grams.

Chemistry

Meprobamate, 2-methyl-2-propyl-1,3-propandiol dicarbamate is synthesized as shown below. 2-methylvaleraldehyde reacts with two molecules of formaldehyde and the subsequent transformation of the resulting 2-methyl-2-propylpropan-1,3-diol into the dicarbamate via successive reactions with phosgene and ammonia.

Meprobamate synthesis

References

http://www.flexyx.com/P/Paxin.html Image from Wikipedia Commons