1. Benzodiazepines and Phenothiazines

2. STRUCTURE:-
BENZODIAZEPINE is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring. 2

3. History:-
The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring cleaning in the lab.
Unexpectedly, the compound showed very strong sedative, anticonvulsant and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium.
Following chlordiazepoxide, diazepam was marketed by Hoffmann–La Roche under the brand name Valium in 1963, and for a while the two were the most commercially successful drugs.
The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses.[1] 3

4. CLASSIFICATION:-
Based on structure benzodiazepines are classified as :-
1,4-Benzodiazepines.
Ex:-oxazepam, nitrazepam, diazepam
1,5-Benzodiazepin-2,4-diones.
Ex:-clobazam, triflubazam
[1,2,4]-Triazolo 1,4-Benzodiazepines.
Ex:-triazolam, estazolam, brotizolam
Imidazolo-1,4-Benzodiazepines.
Ex:-loprazolam 4

5. General synthesis :-
The 2- amino aryl ketone is condensed with a bifunctional, two carbon fragment to give 1,4-benzodiazepin-2-ones. 5

6. Alkylation of 1-unsubstituted molecules:-6

7. DIAZEPAM:- Synthesis:- Properties:-
white to yellow crystalline powder.
sparingly soluble in water, freely soluble
in chloroform and alcohol.
M.P oc.
Synthesis:-
Uses:-
To control anxiety and tension states, the relief of muscle spasm.
It is also helpful in combating withdrawal symptoms in chronic alcoholics.
Metabolism:-
metabolized to nordiazepam.
Half life:-60hrs 7

8. NITRAZEPAM:- 7-Nitro 1,3-dihydro-5-phenyl-2H-1,4-Benzodiazepin-2-one.
Properties:-
yellow, crystalline, powder with out
odor or taste.
It is insoluble in water and sparingly
soluble in chloroform.
m.p.238o
Uses:-
Mainly used as sedative hypnotic
and in the management of
myoclonic seizures.
Half life:-30hrs 8

9. FLUNITRAZEPAM:- 9

10. 1,5-benzodiazepin-2,4-diones
Clobazepam and Triflubazam have
Antianxiety property with mild side
effects. 10

11. [1,2,4]-triazolo-1,4-benzodiazepines:-
compounds in this series have exhibited potent biological activity greater than
1,4-benzodiazepine-2-ones.
Alprazolam is an anxiolytic which has been found to cause significantly less drowsiness than diazepam and which may also be useful for treating Panic disorders and depression.
It is primarily metabolized by hydroxylation either on the C-1 methyl group or at the 4-position of the ring system.
NAME R R1
Triazolam CH3 Cl
Estazolam H H
Alprazolam CH3 H
Adinazolam CH2N(CH3)2 H 11

12. TRIAZOLAM:-
8-Chloro-6(o-chloro phenyl)-1methyl-4H-5-triazolo[4,3-a]-1,4-benzodiazepine
Properties:-
Sparingly soluble in water and alcohol
M.P-235OC 12

13. Imidazolo-1,4-benzodiazepines:-
Loprazolam:- 13

14. Based on duration of action:
1. Short acting drugs (t1/2=6hrs):
eg: triazolam,
midazolam,
brotizolam
2.Medium acting drugs (t1/2=6-12hrs):
Eg: temazepam,
lometazepam,
loprazolam
3.Long acting drugs (t1/2=more than12hrs):
Eg: nitrazepam,
flurazepam,
flunitrazepam

15. SAR:- A B C
In ring A an electron withdrawing group such as Cl, Br, No2,or CF3,CN at position 7.
2. A methyl group is attached to the nitrogen atom in 1 position in ring B. however
substituents at position 1that are metabolically removed are still clinically useful.
ex:-flurazepam,prazepam.
Replacement of the carbonyl function with two hydrogens in the second positiion
gives medazepam less potent than diazepam. Replacement of one of the hydrogen
with a OH on third position lowers activity on the one hand and aids elimination on
the other.
Introduction of a carboxyl function in the third position increases the duration of
action (clorazepate) and also favours formation of a water soluble salts. 15

16. 5. A phenyl substituent at the fifth position α-pyridyl derivative and cyclo alkyl substituents at fifth position give potent compounds.
6.Electro negative substituents such as Cl or F at the ortho position and disubstitution in both ortho positions in ring C
7. Derivatives with additional rings joining the diazepine nucleus at the 1 and 2 positions Are generally more active than the corresponding 1-methylbenzodiazepines.
The positioning of a trizole ring on the α-face of the 1,4-benzodiazepine nucleus, in place of the amide moiety of the benzodiazepinones, enhances its biological activity.
Replacement of the benzene ring by heteroaromatic (e.g: pyrozole) ring resulted In compounds with interesting anxiolytic properties.(ripazepam)
Saturation of the 4,5-double bond reduces potency, as does a shift of the unsaturation into the 3,4-position. 16

17. Pharmacological uses:-
Anxiolytic
Sedative and hypnotic
Anticonvulsant
Muscle relaxant
Alcohol withdrawal 17

18. Mechanism of action:-
Benzodiazepines bind with high affinity to a distinct population of
Binding sites in the brain.
Benzodiazepines do not open the chloride channels by themselves but they act
allosterically to increase the affinity of the receptors for GABA
This increased conductance raises the membrane potential of the neuron resulting in inhibition of neuronal firing.
-        
Binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3 and α5 containing GABAA receptors).
For this reason, benzodiazepines show no affinity for GABAA receptors containing α4 and α6 subunits with an arginine instead of a histidine residue.[1 18

19. Schematic diagram of the (α1)2(β2)2(γ2) GABAA receptor complex that depicts the five-protein subunits that form the receptor, the chloride (Cl-) ion channel pore at the center, the two GABA active binding sites at the α1 and β2 interfaces and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interfac 19

20. Properties continued
     Anticonvulsant activity and amnesic properties are thought to be mediated by α1 receptors2
Benzodiazepines and barbiturates bind more strongly when GABA is also bound to the receptor 20

21. Pharmacological Effects of Benzodiazepines are Concentration-Dependent.
Nanomolar Concentrations
Anxiolytic sedation – via a2 subunit.
Action effectively blocked by flumazenil.
Micromolar Concentrations
Anesthesia – diazepam, midazolam, lorazepam.
Activity due to binding of benzodiazepines to low-affinity site on GABA-A receptor. 21

22. Pharmacokinetics:
Absorption
Distribution
Metabolism
Toxicity 22

23. METABOLISM-

24. Adverse Effects: Benzodiazepines
pharmacology of anxiolytic/sedative-hypnotics
Adverse Effects: Benzodiazepines
Sedation and impairment of performance
Psychomotor skills: driving; engaging in dangerous physical activities; using hazardous machinery, especially during initial phase of treatment
Memory impairment
Anterograde amnesia (desired before surgery, other procedures).
Dose-related, and tolerance may not develop.
Most likely with triazolam . 24

25. NAME Diazepam Oxazepam Nitrazepam Medazepam Flurazepam Prazepam
Lorazepam R1
CH3 H
(CH2)2N(C2H5)2 R2 O H2 R3 OH R7 Cl
NO2
R’2 F 25

26. Phenothiazines 26

27. Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs.
It has the formula S(C6H4)2NH.
This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds.
Derivatives of the parent compound find wide use as drugs.
STRUCTURE:- 27

28. History:- Numbering:-
During second world war, a number of phenothiazine derivatives were Prepared in the laboratories of the French pharmaceutical manufacturer,‘RHONE POULENC’ in Paris
Promazine possess strong anti-histaminic activity.
Synthesis of chlorpromazine, a very large number of phenothiazine derivatives.
Possessing pharmacological actions like sedative and hypnotic potent antihistaminic, tranqulizer, analgesic , urinary antiseptic 28

29. Modifications of the alkyl side chain:-
Maximum potency is retained when there is a three carbon spacing
between the basic amino group and the nitrogen of the phenothiazines
nucleus.
Substitution on the propylene chain of 10-(3-aminopropyl) phenothiazine
may also influence antipsychotic potency.
Methyl group at 1 position
Cyclopropane ring at 1 position
Oxygen introduced at 1-position a 29

30. Modification of basic amino group:- a) effect of 3o amino group
b) alkylation of basic amino group
c) replacement of dimethylamino group of chloropromazine
i) with pyrrolidine, morpholinyl
ii) with piperidyl, piperazine
eg:- 30

31. d) Bridged piperidine derivatives :retains nueroleptic property
e) Introduction of hydroxyl, methyl, groups at 4 position:-increases potency 31

32. Phenothiazine ring substitution:-
f) Esterified with long chain fatty acids to produce slowly absobed, long acting,
Lipophilic prodrugs
Ex:-
Phenothiazine ring substitution:-
a) Substitution at 2 position is optimal for neuroleptic potency.
potency increases in the following order of position of ring substitution:-
1<4<3<2
b) 2-substitution of the phenothiazine nucleus increases the neuroleptic potency
in the following order:-
OH<H<CN<CH3<Cl<CF3
c) Oxidation of the 5 sulfur of antipsychotic phenothiazines decreases activity 32

33. d) Aza-phenothiazines are more effective agents.33

34. Phenothiazines synthesis:-34

35. Treatment of appropriate diphenylamine with a mixture of sulfur and iodine35

36. Promethazine:-
Chemically, promethazine hydrochloride appears as a white to faint yellow crystlline powder that is practically odorless.
Promethazine as the hydrochloride salt is freely soluble in water and somewhat soluble in alcohol. Promethazine is a chiral compound, occurring as a mixture of enantiomers 36

37. Chlorpromazine:-
First synthesized on December 11, 1950, chlorpromazine was the first drug developed with specific antipsychotic action, and would serve as the prototype for the phenothiazine class of drugs, which later grew to comprise several other agents. 37

38. Mechanism of action:-
It is a dopamine inhibitor, increases dopamine turnover in the brain, and stimulates prolatin release. The increased brain turnover of dopamine may be related to its therapeutic effects; it achieves a higher concentration in the brain that in the blood stream.
Metabolism:-
The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for metabolism of chlorpromazine. CYP 2D6 is the main enzyme catalyzing 7-hydroxylation of chlorpromazine, the reaction being partially catalyzed by CYP 1A2.
Excretion:-.
Less than 1% of the unchanged drug is excreted via the kidneys in the urine. In which 20-70% is excreted as conjugated or unconjugated metabolites, whereas 5-6% is excreted in feces 38

39. Piperazine derivatives:-
Synthesis of prochlorperazine and trifluperazine:-
Properties:-
Pale yellow crystalline powder,
with slightly bitter taste
m.p: c
It is more potent than chlorpromazine
It has high prvelance of extra pyramidal effects and therfore mainly used as antiemitic. 39

40. Hydroxyethyl piperazine derivatives:-
Fluphenazine hydrochloride:-
Properties:-
It is a white crystalline powder.
It is soluble in water and alcohol and practically insoluble in ether.
The drug is more potent, exhibits a more prolonged duration of action,
is less sedative. 40

41. Thioridazine:-
Synthesis:- 41

42. It is a slight yellow powder with a bitter taste.
Properties:-
It is a slight yellow powder with a bitter taste.
It is freely soluble in water, chloroform and alcohol and insoluble in ether.
Uses:-
it is effevtive for relif of symptoms of neurotic depressive reactions
Metabolism :-
It is metabolised to active drug mesoridazine 42

43. H generic name i)Promazine .HCl II)Chlorpromazine iii)Triflupromazine
(A)Propyl dialkylaminosidechain:
i)Promazine .HCl
II)Chlorpromazine
iii)Triflupromazine
(B)Alkyl piperidyl side chain:
i)Thioridazine
ii)Mesoridazine
©Propyl piperizine side chain
i)Prochlorperazine
ii)fluphenazine R2 H Cl
CF3
SCH3 R1 43

44. Phenothiazines Pharmacologic effects and mechanism: CNS:
a. neuroleptic effect---
b. antiemetic effect--- inhibit chemoreceptor trigger zone or directly depress the medullary vomiting center.
c. temperature-regulating effect--- produce hypothermia
D1, D5---D1-like receprtors
D D2-like receptors
Antipsychotic drugs probably owe their therapeutic effects mainly to blockade of D2-receptors (lies in midbrain-cortex and midbrain-limbic system ).

45. (2) Autonomic nervous system:
Block α-adrenergic and M-Cholinergic receptors and result in hypotension, dry mouth, constipation and blurred vision.
(3) Endocrine system:
Increase the release of prolactin and decrease corticotropin release and secretion of pituitary growth hormone.

46. Therapeutic uses
(1) treatment of psychotic disorders: schizophrenia, mania, paranoid states, alcoholic hallucinosis.
(2) treatment of nausea and vomiting of certain causes.
(3) anesthesia in hypothermia and artificial hibernation (used with pethidine and promethazine).

47. Adverse Effects: Extrapyramidal motor disturbances:
Parkinson-like symptoms;
akathisia;
acute dystonias.
Treatment: anticholinergic
Other side-effects:
(dry mouth, constipation, blurred vision, hypotension, etc.) are due to block of other receptors, particularly α–adrenoceptors and muscarinic ACh receptors.
Contact dermatitis, blood dyscrasias, obstructive jaundice sometimes occurs with phenothiazines.

48. Adverse Effects Tardive dyskinesia :
Comprises mainly involuntary movements of face and tongue, but also of trunk and limbs, appearing after months or years of antipsychotic treatment. It may be associated with proliferation of dopamine receptors (possibly presynaptic) in corpus striatum. Treatment is generally unsuccessful.
Cardiac toxicity and endocrine effects.

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