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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5484_Библиотеки_им_академика_М_И_Перельмана.pdf
Skeletal Muscle Relaxants 205
13
Skeletal Muscle Relaxants
13.1 INTRODUCTION
Skeletal muscle relaxants are also known as “spasmolytic” agents. Spasticity of muscles is
characterized by the spasms of skeletal muscles in order to increase in tonic stretch reflexes and
muscles weakness. It is associated with cerebral palsi, multiple sclerosis, spinal cord injury, etc.,
results of hyperexcitability of motor neurons. Clinically, spasm is also associated with severe pain in
patient. Spasmolytic drugs or skeletal muscles relaxants relax the skeletal muscles and act as analgesia
both. The first medicinal agent was recognized to show spasmolytic activity, Antodyne or 3-Phenoxy-
1-2-Propaindiol in 1910. Antodyne acts as an analgesic and antipyretic but duration of action of
spasmolytic activity was too short to be clinically useful. Later in 1943, glycerylethers related
antodynes were made a new series of skeletal muscle in relaxants, mephenesin was discovered in
1946 that had ability to depress postsynaptic spinal cord reflexes.
Many CNS depressant agents cause muscle relaxation in the treatment of sprains, ruptures,
arthritis and various muscular disturbances.
13.2 MECHANISM OF ACTION
Skeletal muscle relaxants are functioning to the GABAergic system to depress the skeletal muscles
activity. They decrease the tone of spasticiy via hyperpolarization of G Protein activated K
+
channel.
Some compounds, e.g., orphenadrine acts on NMDA receptors and exhibit antagonist action
(antimuscarinic activity). Cyclobenzaprine drug show muscles relaxant action through antagonism
action on Serotonin 5H T
2
receptors in descending neurons of spinal cord.
206 A Textbook of Medicinal Chemistry
13.3 CLASSIFICATION
A. Glycerol Monoethers Derivatives:
1. Mephenesin (Tolserol®)
HC
3
CH OH
2
CH — OH
HCO
2
2. Carbamol
CH —O—C—NH
22
CH — OH
HC—O
2
R
2
O
R
1
R
1
= H, R
2
= Cl Chlorphenesin (Maolate®)
R
1
= OCH
3
,
R
2
H Methocarbamol (Robaxin®)
Fig. 13.1
B. Alkanediols Derivatives:
1. Meprobomate (Equanil®)
CH —O—C—NH
22
CH —C—C H
337
CH —O—C—NH
22
O
O
2. Carisoprodol (Rela®)
CH —O—C—NH
22
HC—C—C H
337
CH — O — C — NHCH
2
O
O
CH
3
CH
3
Skeletal Muscle Relaxants 207
3. Metaxolone (Skelaxin®)
H
HC—N
2
C O
CH — O
HC—O
3
CH
3
CH
3
Fig. 13.2
C. Benzazole Derivative:
1. Chlorzoxazone (Paraflex®)
Cl
C O
N
H
O
Fig. 13.3
D. Imidazoline Derivative:
1. Dantrolene (Dantrium®)
CH N — N
O
ON
2
NH
O
O
Fig. 13.4
E. Miscellaneous:
1. Orphanadrine citrate (Norflex®)
CHO — CH — CH — N
22
CH
3
CH
3
CH
3
2. Cyclobenzaprine (Flexaril®)
CH — CH — CH — N
2
CH
3
CH
3
2
208 A Textbook of Medicinal Chemistry
3. Baclofen (Lioresal ®)
Cl
CH — NH
22
CH
CH — COOH
2
Fig. 13.5
4. Benzodiazepines : Diazepam, Fletazepam (Discused in Chapter 12)
13.4 SPECIFIC DERIVATIVES
13.4.1 Glycerol Monoethers Derivatives
1. Mephenesin (Tolserol
®
): is 3-(o-methyl phenoxy)-1,2-Propanediol
CH
2
O — CH — CH — CH OH
22
OH
Fig. 13.6
Mephenesin is a potent skeletal muscle relaxant. It cause the skeletal muscle relaxation of hyper
tonic muscles to minimize the sensory stimuli. It is also significantly depressed the superficial
reflexes. Mephenesis is suggested to the treatment of muscular spasm, hyperkinetic condition. It is
also used in the treatment of anxiety and tension states.
Synthesis:
CH
3
ONa
+ Cl — CH — CH — CH — OH (condensation)
22
C
CH
3
O — CH — CH — CH OH
22
Sodium-O-Cresolate
a-chlorhydrin Mephenesin
2. Chlorphenesin (Maolate
®
):- 3-(p-chlorophenoxy)-1, 2-propanediol-1-carbamate
Cl
O — CH — CH — CH — O CO NH
222
OH
Fig. 13.7
Chlorphenesin is a potent spasmolytic agent, due to presence of secondary hydroxyl group. It
undergoes active metabolism via glucoronidation. Chlorphenesis is used for the symptomatic relief
of muscular spasm as well as it exhibits antifungal activity.
Skeletal Muscle Relaxants 209
Synthesis:
OH
Cl
OH + Cl — CH — CH — CH OH
22
Cl
OCH — CH — CH — OH
22
OH
Phosgene
P-chlorophenol
1-chloropropan-2, 3-diol
Cl
Chlorphenesin carbamate
O—CH —CH—CH —O—C
22
O
OH
NH
2
Cl
OCH —CH—CH —O—C—Cl
22
O
NH
3
OH
Fig. 13.8
3. Methocarbamol (Robaxin
®
): 3-(O-methoxy phenoxy)-1, 2-propandiol-1-carbamate
OCH — CH — CH — OCONH
222
OH
OCH
3
Fig. 13.9
Methocarbamol is potent centrally acting muscles relaxant. It significantly relieves from muscles
spasm. It is also used in the treatment of Parkinson’s disease.
Synthesis:
OH
+ Cl — CH — CH — CH OH
22
O — CH — CH — CH OH
22
OH
Phosgene
Catechol monomethyl
ether
1-chloropropane-2, 3
diol
Methocarbamol
OCH —CH—CH —O—C—NH
22 2
O
OH
OCH —CH—CH —O—C—Cl
22
O
NH
3
OH
OH
OCH
3
Alkylation
Amination
OCH
3
OCH
3
OCH
3
Fig. 13.10
13.4.2 Alkanediols Derivatives
1. Maprobamate (Equanil®): 2-methyl-2-propyl-1,3-propandiol dicarbamate.
210 A Textbook of Medicinal Chemistry
H N — CO — O — H C — C — CH — O — OCNH
2222
CH
3
CH CH CH
223
Fig. 13.11
Maprobamate is generally sedative and hypnotics. It is believed that its action exerts on particular
area of brain in respect of conductivity. It shows anticonvulsant activity beside that muscles relaxant
activities. It is also used as a mild to moderate tranquilizer in the treatment of anxiety and mental
disorder.
Synthesis:
HOH C — C — CH OH
22
CH
3
CH CH CH
223
ClCOOH C — C — CH OOCCl
22
CH
3
CH
37
2-methyl-2-m-propyl-1-,3-propandiol Chloroformate diester
(Ammonolysis)
Maprobamate
Toluene/Phosgene 0°C
N, N-Dimethyl aniline
Fig. 13.12
5. Metaxolone (Skelaxin®):- 5-[(3,5-xylyloxy)Methy)]-2-oxazolidinone
Metaxolone significantly reduces the muscle tone. It is used for the relief of acute muscle spasms
caused by various injuries or strains.
Synthesis:
Cl
Cl
OH
+ Cl — CH — CH — CH OH
22
OH
Cl
Cl
O — CH — CH — CH OH
22
OH
Alkylation
HC
3
HC
3
O—CH
2
O
O
N
H
NH
2
(i)
(ii) Alkylation
C O
NH
2
1-Chloropropane-2,3-diol
3,5-Dichlorophenol
Metaxalone
(Urea)
Fig. 13.13
Skeletal Muscle Relaxants 211
13.4.3 Benzazole Derivative
1. Chlorzoxazone (Paraflex
®
):- 5-chloro-2-benzoxalinone
Chlorzoxazone is a potent centrally acting skeletal muscle relaxant. It inhibits the postsynaptic
reflexes both within spinal cord and subcortical area of brain. It is used in the treatment of severe
painful muscle spasm. It is also suggested in the treatment of spondilytis, sprains and muscles
strains.
Synthesis:
Cl
NH
2
OH
Cl
O
N
|
H
O
COCl
2
Phosgene
2-amino-4-chlorophenol
Chlorzoxazone
Fig. 13.14
13.4.4 Imidazolin Derivative
2. Dantrolene (Dantrium
®
): 1-[[5-(p-Nitrophenyl)-furfulidene]-amino]-hydantoin sodium salt
hydrate.
Dantrolene is hydantoin derivative which acts centrally and peripherally to reduce spasticity.
Dantrolene is used in the treatment of spinal cord injury. Stroke cerebral palsy and multiple sclerosis.
O
N
NH
Na
O
CH N
–
+
ON
2
O
Fig. 13.15
13.4.5 Miscellaneous Agents
Beclofen (±) (Lioresa
®
): β-(aminomethyl)-p-chlorohydro-cinnamic acid.
Beclofen is the derivative of gamma aminobutyric acid because it is structurally similar to GABA.
H N — H C — CHCH COOH
22 2
Cl
Fig. 13.16
212 A Textbook of Medicinal Chemistry
Thus, it shows agonist activity at the size of GABA
B
receptor via mechanism G-Protein activated
K
T
channel (hyperpolarization). Beclofen is one of the most common used antispastic drugs. Beclofen
is employed by oral administration and has minimum hepatic metabolism. It is also given to the
patient via parentral and intrathecal administration.
Synthesis:
Cl
CH CH — COOC H
25
Cl
CH NO
32
Nitromethane
CH — NO
22
CH
H C — COOC H
225
(Ester derivative)
Reduction
[H]
Cl
CH — NH
22
CH
CH — COOC H
225
NaOH
Cl
CH — NH
22
CH
H C — COOH
2
Beclofen
4-chlorocinnamic acid
Fig. 13.17
13.5 NEWER AGENTS
1. MS-322 : (R)-(+)-3-phenyl-5-2-(1-pyrrolidinyl methyl)-butyryl isoxazole hydrochloride.
Recent studies on centrally acting muscle relaxants depicted a newer agent MS-322 that reduced
spinal reflex potential in acutely spinalized rats close dependently. It shows inhibitory effects on
Polysynaptic and dorsal root reflexes were more marked than monosynaptic reflexes therefore it
shows better muscle relaxant activity.
N
O
N
O
C
H
CH
3
HCl
Fig. 13.18
2. Silperisone: N-[(dimethyl-4-fluorobenzyl silyl)-methyl]-piperidine HCl.
Silperisone is organo silicon compound with centrally acting muscles relexant activity. Studies
showed that silpersone cause CNS depressant or motorside effect than other drug tolperisone. It is
an effective to suppress monosynaptic and postsynaptic spinal reflexes.
1
General Pharmacology (1998) The Vascular System, Vol. 30 (3), 393-398.
Skeletal Muscle Relaxants 213
F
CH
3
CH — Si — CH — N
22
CH
3
HCl
Fig. 13.19
3. Tolperisone: 2-methyl-1-(4-methyl phenyl)-3(1-piperidyl)-propane-1-one
Tolperisone is potent centrally acting muscles relaxant it is much more suitable for cerebral
atherosclosis for better movement for treating extra piramidal movement disorders.
N
HCl
HC
3
O
CH
3
Fig. 13.20
4. Lamperison .HCl (NK-433): (–)-(R)-2-methyl-3-(1-pyrrolidinyl)-4’-tri-fluoromethyl
propiophenone monohydrochloride.
It is a novel centrally acting muscle relaxant which inhibits monosynaptic tonic vibration reflex.
but it is a weak inhibitor on post-synaptic reflexes.
F—C—F
C O
N
F
HC
3
Fig. 13.21
EXERCISE
1. Define spasmolytic agents or centrally acting muscle relaxants.
2. Classify centrally acting muscle relaxants and explain their mechanism of action.
2
CNS—Reviews.(2006), Vol. 12 (3-4), 218–235.
3
Ozawa et al. (1996) Eur. J. Pharmacol. 298 (1) 57, 62
214 A Textbook of Medicinal Chemistry
3. Write the synthesis and MOA with their uses of Glycerol monoether derivatives.
4. Classify alkanediol derivatives of skeletal muscles relaxants. Give their mechanism of action
and uses.
5. Write following drugs synthesis.
1. Beclojen
2. Mephensin
3. Chlorzoxazone
4. Metaxolone
6. What are the recent developments in skeletal muscles relaxants? Explain it.