CNS depressants CNS depressants can be classified into: 1- Sedative hypnotics. 2- CNS depressants with skeletal muscle relaxant properties. 3- Anticonvulsants. 4- Anxiolytic drugs. 5- Antipsychotics. 1

3- Central Nervous System Depressants with Skeletal Muscle Relaxant Properties These are agents used in acute muscle spasms and in spasticity. Uses: To relief muscle spasticity caused by musclo-skeletal or spinal cord trauma, brain lesions or brain diseases. Disk syndrome. Arthritis. Inflammation of joints. Low back pain. Classification Propanediol carbamate derivatives. Aryl glycerol monoether. Miscellaneous 2

1- Propanediol carbamate derivatives The propanediol carbamates, meprobamate, and carisoprodol, little used as antianxiety agents. They are less effective than BZD as anxiolytics. Carisoprodol is used as M. relaxant. if used; long term or high doses, can cause physical dependence SAR For alc. Series; depressant potency increases 1.Up to 8Cs 2.Branching of alkyl gp 3.Replacement of H in alkyl gp by X 4.Carbamylation 3

2- Aryl glycerol monoether ; Mephenesin is weakly active and short lived because of facile metabolism of the primary hydroxyl group. Mephenesin carbamate: Carbamylation of the primary hydroxyl group yields increased activity. Chorlphenesin: increases the lipid/water partition coefficient and seals off the para position from hydroxylation Chlorphenesin Carbamate: p -chloro substituted and 1-carbamate 4

3- Miscellaneous Baclofen: (RS)-4-amino-3-(4 ` -chlorophenyl) butyric acid It is an analog of GABA and exerts its action by stimulating GABA B receptor subtype, Antispastic involving diseases of the spinal cord. Baclofen 5

4- Anticonvulsant or Antiepileptic Drugs Types of seizures (Epilepsy): 1.Generalized seizures Generalized tonic-clonic seizures (grand mal) Non-convulsive seizures or absence (petit mal) seizures 2.Unilateral seizures (involve one entire side of the body). 3.Partial (or focal) seizures: Simple focal Complex focal 4.Erratic seizures (of the newborn). 5.Unclassified seizures (sever seizures associated with a high mortality). 6 The epilepsies: are a group of disorders characterized by chronic, recurrent, paroxysmal changes in neuralgic function caused by abnormalities in electrical activity of the brain. Classification of anticonvulsant drugs: I-Anticonvulsant drugs containing ureide structure. II-Benzodiazepines III-Miscellaneous.

I-Anticonvulsant drugs containing ureide structure 7 Class of compounds X Barbiturates Phenobarbital Mephobarbital tonic - clonic seizures Hydantoins Phenytoin Ethotoin Mephenytoin tonic-clonic seizure Oxazolidinediones Trimethadione absence seizure Succinimides Ethosuximide Methsuximide Phensuximide absence seizure X Ureide Structure Changes in X group cause significant changes in type of seizures controlled Chemical Drug Classes MOA of anticonvulsants: (a)Enhancement of (GABA) inhibitory neurotransmission, (b)Attenuation of excitatory) neurotransmission in the brain.

General structure activity relationships: 1.The substitution pattern at C 5 of the hydantoins and oxazolidinediones or C 2 of the succinimides determine the type of antiseizure activity. Hydantoins with at least one C 5 phenyl group are the drugs of choice in generalized tonic-clonic seizures. The diphenyl substitution pattern increases potency of anti-grand mal than single substitution. Oxazolidinediones substituted at C 5 with small alkyl chain (methyl or ethyl) are more effective against petit mal, less effective against grand mal seizures. The most potent antipetit mal succinimides have small alkyl groups at C 2. 2.Whereas, Oxazolidinediones are toxic, succinimides are safer as alternative for absence seizures (petit mal). 8

1) Barbiturates Although sedative-hypnotic barbiturates display anticonvulsant properties, only phenobarbital and mephobarbital display anticonvulsant selectivity for use as antiepileptic. Both agents are effective against generalized tonic-clonic and partial seizures. The metabolism of phenobarbital involves p-hydroxylation, followed by conjugation Mephobarbital (N1-CH 3 ); It is metabolized by N-demethylation to phenobarbital, to which it owes its activity. 9 Phenobarbital

2) Hydantoins (imidazolidine-2,4-dione) They are close structural relatives of the barbiturates, differing in lacking the 6-oxo moiety. They are useful as anti generalized tonic-clonic (grand mal) rather than anti-absence (petit mal). 10 Fosphenytoin, a prodrug of phenytoin, was developed and marketed to avoid vein irritation, tissue damage, and muscle necrosis associated with parenteral phenytoin administration.

Synthesis of 5,5-disubstituted hydantions: 5,5- Disubstituted hydantions can be synthesized according to the following general scheme: 11

3) Oxazolidinediones Replacement of NH group at position 1 of the hydantoins with oxygen yields oxazolidine-2,4-diones. 12 Trimethadione is the prototype structure of antiabsence (anti-petit mal) compounds. Metabolized by N-demethylation to dimethadione which is active. SE: aplastic anemia and bone marrow depression which limit its clinical use. Mechanism: possible blocking action on calcium T-type channels General Structure Developed in the late 1940’s to control absence seizure (petit mal) highly toxic ineffective in the treatment of partial seizure Dimethadione N-demethylation

4) Succinimides ; 2,5-pyrrolidinedione derivative Phensuximide is used in absence seizures. However, due to the phenyl group, it has some activity against generalized seizures. Methsuximide is used in absence and partial seizures. Ethosuximide is the most effective. It is the drug of choice for typical absence seizures (less toxic than trimethadione). 13 Mechanism: possible blocking action on calcium T-type channels treatment of absence seizure (petit mal), ineffective in the treatment of partial seizure. Less toxic than oxazolidinediones

II-Benzodiazepines Diazepam, clonazepam and chlorazepate dipotassium are used as anticonvulsants. 14

III-Miscellaneous Primidone (Primaclone) 5-Ethyl-5-phenyl perhydropyrimidine-4,6-dione. It is the deoxyanalogue of phenobarbital. It is used to control generalized tonic-clonic seizures. Its anticonvulsant effect may be due to its oxidation to phenobarbital. 15 Gabapentin analogue of GABA adjunct for use against partial seizures

b) Carbamazepine;5-H-Dibenz[b,f]azepine-5-carboxamide. It is 1,1-diphenylurea. ( Iminostilbenes) The two phenyl groups on the nitrogen fit the pattern of anti-generalized tonic-clonic activity. It is a drug of choice in generalized tonic-clonic and partial seizures. The drug causes bone marrow depression and haematologic injury (aplastic anemia). 16 Synthesis: Mechanism: blocking action on voltage-dependent sodium channels

17 Metabolism: Metabolism proceeds through epoxide formed at the cis- stilbene double bond, which has marked activity, then it is converted in human to the trans-dihydroxycarbamazepine (excreted in the urine).

18 c) Oxcarbazepine ((10,11-Dihydro-10-oxo-5H-dibenz[b,f]-azepine-5 carboxamide)). It is a derivative of carbamazepine with fewer side effects, due to lack of epoxide formation. During designing this drug, the olefinic double bond in carbamazepine is reduced to -CH 2 -CH 2 -, and then one CH2 converted to the ketone. Metabolism: The drug is metabolized in the liver to10,11- dihydro-10-hydroxy-carbamazepine which is excreted in urine.

d) Valproic acid (Depakene) 2-Propylpentanoic acid Valproic acid has good potency and is used against several types of seizures. It is a drug of choice for typical and atypical absence seizures and in absence seizure with generalized tonic-clonic seizures. 19 Mechanism: blocking action on voltage-dependent sodium channels

Metabolism: Metabolism is by conjugation of the carboxylic acid group and oxidation of the hydrocarbon chains. 20