.Hypnotics and sedative drugs are used to produce drowsiness and promote sleep.
.These drugs depress the CNS.
.A sedative drug decreases activity, excitements whereas a hypnotic drug produces drowsiness and facilitates the onset and maintenance of sleep as a natural sleep.
Classification
.According to chemical structures, sedative and hypnotics may be classified into following category:-
A)-Barbiturates:- It is a cyclic ureids.
Generic name R1 R2 R3 Barbital -Et - Et -H Long duration of action
Mephobarbital (Methyl -Et -C6H5 -Me Long duration of action phenobarbitone)
Phenobarbital -Et - C6H5 -H Long duration of action Allobarbital allyl allyl -H Intermediate duration of action
Amobarbital -Et -C5H11 -H Intermediate duration of action
Probarbital -Et -CH(CH3)2 -H Intermediate duration of action
Pentobarbital -Et -CH(CH3)-(CH2) 2CH3 -H Short duration of action Methohexital -allyl -CH(CH3)-C≡C-CH2CH3 -1-Me Short duration of action Hexobarbital -Me -1-Me Short duration of action
Thiopental (2-C=S) -Et -CH(CH3)-(CH2) 2CH3 -H Ultra Short acting barbiturates
B)- Benzodiazepines:-
R1 O 9 N 1 8 2 3 4 5 R 7 N 2 6
R3
Drug R1 R2 R3
Flurazepam -CH2CH2N(C2H5)2 -Cl -F Temazepam,(3-OH) -Me -Cl -H
Quazepam,(2-C==S) -CH2CF3 -Cl -F
C)- Non-Barbiturates and Non- Benzodiazepines:-
Ex.-
C2H5 C6H5 O N O H
• Chloral hydrate
Cl OH Cl C OH H Cl
CH3
O H O H H H C O CH 3 3 SAR of Barbiturates
O
4 R1 5 H N R2 3
O 6 2 O N1
R3
• In general , structural changes that in case the lipid solubility, decrease duration of action, accelerate metabolic degradation and increase hypnotic potency. • If one hydrogen is available at position-5, tautomerization to a highly acidic trihydroxypyrimidine can occur. consequently, the compound is largely in the anionic form at physiological pH, with little non ionic. Lipid soluble compound available to cross the BBB. • At position-5 of the barbiturates both the hydrogen atoms must be replaced by alkyl/aryl substituents because hypnotic activity increases with lipid solubility until the total no. of carbon atoms for both substituents at C-5 is between 6 and 10. Further increase in the sum of the carbon atoms, decreases hypnotic activity in spite of further increase in lipid solubility. Ex.- Phenobarbital, Mephobarbital • The branched chain isomer has greater lipid solubilty and hypnotic activity and shorter duration of action than the straight chain isomer. Ex.- Pentobarbital is more potent hypnotic than amobarbital. • The unsaturated allyl derivatives are more hypnotic than the saturated analogues with the same no. of carbon atoms. Alicyclic or aromatic substituents are more potent than the aliphatic substituents with the same no. of carbon atoms. • Methylation of nitrogen at position-1, increases lipid solubility, and shortens duration of action. Ex.- Methohexital, Mephobarbital • Introduction of the polar groups, such as hydroxy, amino, carbonyl or keto into alkyl side chain decreases lipid solubility and abolishes hypnotic activity. • Replacement of oxygen by sulphur at position-2, leads to increased lipophilicity and very rapid penetration of blood brain barrier(BBB). Ex.-Thiopental
Mechanism of action of Barbiturates At low concentration, Barbiturates either have a γ-amino butyric acid (GABA) like action or enhance the effects of GABA (Inhibitory neurotransmitter). Barbiturates activate GABA receptors in high concentration. When GABA receptors are activated, chloride channels open.
Chloride enters the cell, hyperpolarises it, and produce decrease excitation. GABAA receptors are part of supramolecular complex that also include the benzodiazepine receptor and a Picrotoxin site. Barbiturates bind to Picrotoxin site and decrease chloride ion flux and produce an increase chloride ion concentration. Greater the affinity of a Barbiturates for the Picrotoxin binding site, greater is its potency.
Synthesis of Diazepam
NH H 2 O N O Pyridine Cl CH CH OC-CH NH + 3 2 2 2 cyclized O -H2O Cl N -C2H5OH
2-Amino-5-chloro- benzophenone
Methylation (CH3)2SO4/C2H50Na
CH 3 O N
Cl N
Diazepam
Note:-
• Diazepam is metabolized by N-demethylation to nordiazepam. • It is used for the control of anxiety and tension states, the relief of muscle spasm (Involuntary muscular contraction).