Directacting Muscle Relaxants

The only drug of this type that is widely recognized is dantrolene.

Dantrolene: Dantrolene, 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazo-lidinedione (15.2.2), is synthesized by reacting 4-nitrophenyldiazonium chloride with fur-furol, forming 5-(4-nitrophenyl)-2-furancarboxaldehyde (15.2.1), which is reacted further with 1-aminohydantoin, to give the corresponding hydrazone, dantrolene (15.2.2) [25,26].

Dantrolene is a drug that causes spastic muscle contraction. Unlike other muscle relaxants, it has a direct effect on the contractile mechanism by interfering in the process of calcium ion release from the sarcoplasmic reticulum. This results in a lack of coordination in the mechanism of excitation—contraction of skeletal muscle, which has a greater effect on fast muscle fibers than on slow muscle fibers. Dantrolene is used for controlling the onset of clinical spasticity resulting from serious clinical cases such as wounds, paralysis, cerebral palsy, and disseminated sclerosis. Synonyms of this drug are dantrium and danlen.

Unfortunately, paralysis of skeletal muscle attained by using curare-like compounds, in the majority of cases, is not useful for general conditions of spasticity accompanied by the CNS involvement, as well as for local injuries or inflammation. Of course, neuromuscular blockage reduces spasms; however, it is accompanied by loss of voluntary movement.

In conditions of muscle spasticity, there need to be drugs capable of relieving painful muscle spasms that do not take away the ability of voluntary muscle contraction and that do not hamper brain function.

Many CNS depressants cause muscle relaxation. Among these it is noteworthy to mention alcohol and barbiturates, which, however, are not used for this purpose because they cause significant sedation and other effects. The search for selective CNS-active substances responsible for achieving muscle relaxation led to the formation of a number of interesting compounds proposed for clinical applications; however, not one of them could completely satisfy the necessary requirements. Moreover, muscle relaxants acting by affecting the CNS are widely used in treating sprains, ruptures, arthritis, and other muscular disturbances. Included is a large het-erogenic group of chemical compounds that have an effect on the spinal cord and suppress monosynaptic and polysynaptic reflexes. Among these are baclofen, cyclobenzaprine, cariso-prodol, methocarbamol, chlorphenesin, chlorzoxazone, orphenadrine, and diazepam.

Baclofen: Baclofen, 4-amino-3-(4'-chlorophenyl)butyric acid (15.3.5), is synthesized in two ways. According to the first, 4-chlorobenzaldehyde is condensed with two moles of acetoacetic ester, giving the product (15.3.1), which initially undergoes alkaline hydrolysis and decarboxylation forming 3-(4-chlorphenyl)glutaric acid (15.3.2). Dehydration of this gives 3-(4-chlorophenyl)glutaric acid anhydride (15.3.3), and further treatment with ammonia gives the corresponding glutarimide (15.3.4). Reacting this with an alkaline solution of a halogen (Hofmann rearrangement) gives baclofen (15.3.6) [27,28].

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