DRUGS ACTING ON CNS- CNS STIMULANTS AND PSYCHEDELICS

CNS STIMULANTS AND PSYCHEDELICS

The drugs that produce stimulation of central nervous system and enhancement in excitability of different portions of the brains or the spinal cord.

The CNS stimulants include analeptics, antidepressants, central sympathomimetic agents (Psychomotor stimulants). Some times CNS stimulants lead to convulsions so they are limited therapeutic value because of their convulsant activities and side effects.

Classification :

1. Analeptics – Picrotoxin, Nikethamide, Etamivan, Pemoline Pentylene t e t r azole( Pen tetrazole), Doxopram, Bemegride, Strychnine.


2. Methyl xanthines – Caffeine, Theophylline, Theobromine, Aminophylline, Etophylline, Proxyphylline.


3. Central sympathomimetic agents ( Psychomotor stimulants) –
   Amphetamine, Methamphetamine, Phentermine, Benz phentamine, Chlorpentermine, Ferfluramine, Chlortermine, Phenmetrazine, Phendimetrazine, Mazindol, Methyl phenidate.


4. Mono amino oxidase Inhibitors (MAO – inhibitors) – Phenelzine, Isocarboxazid, Tranyl cypromine, pargyline, clorgyline.


5. Tricyclic Antidepressants – Imipramine, Desipramine, Amitryptyline, Nortriptyline, Protriptyline, Trimipramine, Doxepin, Maprotiline.


6. Psychedelics –
   1. Indole ethyl amines – Bufotenine, Psilocybin, Psilocyn
   2. 2 – Phenyl ethylamines – Mescaline
   3. Agents have both indolethylamine and phenyl ethylamine – (+) Lysergic acid, Diethylamide (LSD).
   4. Dissociative agents – Phencyclidine (PCP)
   5. Depressant - Intoxicant – Tetra hydro cannabinol (THC)

I.Analeptics:

Analeptics are agents which stimulate various areas of the central nervous system. These are mainly used for the treatment of respiratory depression resulting from overdose of depressant drugs. So these are used as respiratory stimulants.

An excessive dose of analeptics may result a wide – spread stimulation of the brain that may ultimately cause convulsions.

Mechanism of action for analeptics

1. Some drugs block post synaptic inhibition (Strychmine) or pre synaptic inhibition (Picrotoxin).


2. Some drugs acts as GABA ontagonist (Picrotoxins bemegride) or release prostoglandin and also decrease energy levels (rentetrazole)
   

Nikethamide Synthesis

Doxapram Synthesis

II.Methyl Xanthines

III. Psychomotor Stimulant

Dextro amphetamine Synthesis


SAR for central sympathomimetic agents :

1. Any decrease in distance between aromatic ring and heterocyclic nitrogen decrease the activity.
2. The branched CH3 group or similar substitution is important for activity, since it provides resistance to enzymatic is activation by steric protection of the amino group.
3. In phenidate series, activity is maximal at the methyl ester.
4. In morpholine series aromatic substitutions and replacement of ring by heterocyclic groups decrease the activities.

Mechanism of action

1. They inhibit reuptake mechanisms for several biogenic amines.


2. They enhance neuronal release of catecholamines.


3. They stimulate a - adrenergic receptor and inhibit mono amino oxidase is higher concentration.

IV.Mono amino oxidase Inhibitors

Tranyl Cypromine

SAR for mono amino oxidase inhibitors

1. Cyclo alkyl substituents has equal potency with corresponding N- alkyl group Di alkyl substituted hydrazine (R2NNH2) devoid of significant activity.
   
2. Hydroxyl alkyl hydrazines are usually less effective MAO inhibitors than the corresponding alkyl hydrazines.
   
3. Aromatic ring substituents with polar groups decrease the activity Un substituted hydrazides (RCONHNH2) do not inhibit MAO.
   
4. Mono substituted hydrazides may enhance MAO inhibitory activity.

V. Tricyclic Anti depressant

Imipramine

Desipramine

Amitriptyline

Doxepin


SAR for Tricyclic Antidepressants

1. The maximum antidepressant activity results on separation of the basic amino group from tricyclic nucleus by propylene bridge. The chain exceeding propyl group decrease activity.
   
2. 3 – chloro derivative has less active than imipramine.
   
3. O-(CH3)2 derivative has equal potency.
   
4. Nuclear di substitution decreases the activity.
   
5. Piperazine propyl derivative are found to be ineffective
   
   For Dibenzo Cyclopentane derivatives

1. 3 – Cl substitution enhance potency while a 3-CH3 group diminish CNS depressantDouble bond between 10 &11 positions increases activity
   
2. The higher central ring homologue (octane) is more effective.
   
3. At position 11 the carbon is substituted by O,S,SO are clinically effective anti depressant
   The bridged central ring also possess power full anti depressant activity.
   
   VI. Psychedelics

Psychedelics are agents which producing an increased awareness and enhanced perception of sensory stimuli. These are mind expanding drugs.

These drugs can produce anxiety, fear, panic, hallucinations resembling to a psychosis. Hence they are called as hallucinogens and psychoto mimetics.

Indole ethyl amines
2 – Phenyl ethylamines
Agents have both indolethylamine and phenyl ethylamine



Dissociative agents – Phencyclidine (PCP)

Depressant - Intoxicant – Tetra hydro cannabinol (THC)

Mechanism of action of Psychedelics

1. They induce or accelerate the production of hallucinogenic metabolites for noradrenaline.
   
2. They may cause charges in cerebral blood flow and permeability of cerebral capillaries.
   
3. They alters the levels of adrenal corticoidal and thyroid hormones or changes in synthesis or metabolism of serotonin, nor epinephrine, acetyl choline or other potential transmitter.
   
4. Since serotonin is an inhibitors neurotransmitter, the removal of its inhibition could lead to behavioral changes.
   
5. These drugs may disrupt cerebral energy production or utilization in such a fashion that it alters the behaviours.

DRUGS ACTING ON CNS-ANTI CONVULSANT DRUGS

ANTI CONVULSANT DRUGS (OR) ANTI EPILEPTIC DRUGS

Epilepsy is a collective term for a group of chronic CNS disorders having in common, sudden and transitory seizers of loss or disturbance of consciousness with characteristic body movements (convulsions) and some times with autonomic hyperactivity.
The principal types of epilepsy are
1. Grandmal epilepsy:
It is normally characterized by complete loss of consciousness followed by transient muscular rigidity and clonic convulsions in all voluntary muscles.
2.Petitmal epilepsy :
It is usually momentary loss of consciousness. There is free of convulsions and occasionally blinking movements of eyelids and jerking movements of the head and arms.
3.Psychomotor epilepsy :
It is characterized by attacks with out convulsions lasting from 2-3 mts. It display mental apathy and sudden irrational and destructive attitude.
4.Myoclonic seizers :
It is characterized by jerky muscular movements of head, limbs or body as such. The duration of attack remains near about one second and reappears at about 5 secs intervals for 1 min. It is rapid rhythmic movement.
Anti Convulsants:
Anti Convulsant drugs are also termed as antiepileptic drugs are drugs which selectively depress the CNS and prevent or control the epileptic seizers.
The drugs are adequate and impressive control and management of CNS disorders essentially characterized by recurrent transient attacks of disturbed brain function which ultimately give rise to motor(convulsive), sensory(seizures) and psychic sequence of events.

CLASSIFICATION

1. Barbiturates – Phenobarbital, Mepho barbital, Metharbital


2. Hydantoins – Phenytoin, Mephenytoin, Ethotoin


3. Oxazolidine dione - Trimethadione, Paramethadione


4. Succinimides – Phen suximide, Methsuximide, Ethosuximide


5. Urea derivatives – Phenacemide, Carbamezepine


6. Benzodiazepines – Clonazepam, Diazepam, Chlorazepate


7. Miscellaneous – Primidone, Valproic acid, Gabapectin, Felbamate.
   

1. BARBITURATES

2. HYDANTOINS

Synthesis of phenytoin

3.OXAZOLIDINEDIONES

Synthesis of Trimethadione

4. SUCCINIMIDES

Synthesis of Ethosuximide

5.UREA DERIVATIVES

i. Phenacemide

2.Carbamazepine

6. BENZODIAZEPINES

Clonazepam

7. MISCELLANEOUS

i.Pyrimidone

ii. Valproic acid

Structure Activity Relationship

For Barbiturates

1. Phenyl or other aromatic substituents at 5th position is essential for good activity.


2. 5,5 diphenyl derivative has less active than phanobarbitone.


3. N-substitutions also increases the antiepileptic activity.


4. 5,5-dibenzyl barbiturates causes convulsions.

For Hydantoins

1. Phenyl or other aromatic substituents at 5th position is essential for good activity.


2. Alkyl substitution at 5th position may contribute to sedation.


3. Some Thio hydantoins, Dithio hydantoins and 1,3-disubstituted hydantoins exhibit activity against chemically induced convulsions and ineffective against electroshock induced convulsions.

For Oxazolidine diones

1. The nature of substituents at 5th position is essential for good activity.


2. The lower substituents tend towards anti-petitmal epileptic activity and aryl towards anti-grandmal epileptic activity.


3. N-alkyl substituents does not affect the activity, because the N-dealkylated metabolites are active anticonvulsant agents.


4. Alkylation of imido nitrogen is more active, because it increase partition coefficient and prevent the dissociation of imido nitrogen and more distribution to CNS.

For Succinimides

1. Meth suximide and phen suximide have phenyl substituents at 3rd position are active ineffective against electroshock induced convulsions.


2. N-methylation decreases the activity against electroshock induced convulsions and more activity against chemically induced convulsions.


3. Alpha-methyl alkoxy phenyl succinimides and alkoxy benzyl succinimides were active anti convulsants.

For Benzodiazepines

1. The electron withdrawing groups at 7th position increases antiepileptic activity and electron donating groups at 7th position increases antiepileptic activity.


2. A phenyl group at 5th position is necessary for good activity. But the halogen substituents in phenyl group in ortho position increase the activity.


3. The electron withdrawing groups at ortho or diortho positions at 5-Phenyl group increases antiepileptic activity while any substituent on meta or para position of 5-Phenyl group decreases antiepileptic activity.


4. Methyl substitution at 1st position increases the activity.

Mechanism of action

1. The generation of seizures is due to excessive discharge of neurotransmitter in CNS.The anti convulsant drugs increase the level of serotonin in brain which causes non specific depression of CNS functions and controls the release of neurotransmitters.


2. Gama Amino Butyric Acid(GABA) levels in brain is also important to prevent the speed of seizures. So anti convulsant drugs increase the level of GABA in brain.


3. Anti convulsant activity of barbiturates is attributed to their ability to exert conformational rearrangement of oxidative enzymes essential for brain respiration.


4. Many carbonic an hydrase inhibitors have Anti convulsant activity by decreasing the cerebral respiration due to excess Co2 depress the nerve function.


5. Anti convulsant drugs usually display various combined activities on the neuronal function such as act on ion channels and maintain the neuronal membrane, the resting potential having range of -50 mv to -80 mv between inside (K+) and outside (Na+ & Cl-) of the cell.


6. GABA binds to GABA A and GABA B receptors. The oscillation rhythms in epilepsy caused by GABA A receptors. Therefore the drugs potenciate GABA mediated inhibitors or to affect the GABA concentration in brain.
   
   
   

DRUGS ACTING ON CNS- ANTI PSYCHOTICS

ANTIPSYCHOTICS [TRANQUILIZERS (OR) NEUROLEPTICS]

Antipsychotic drugs are also CNS depressants. Anti psychotic drugs are drugs which are used in the treatment of mental disease that are characteristic of the psychoses which is a behavioral disorder.
These agents have the capacity to sedate or tranquilize the emotional expressions , aggressive and impulsive behavior and influence being free to mind from disturbance and thus calms the mind with out inducing sleep.
Psychosis: The psychoses are inhibition of sharpens or alter the behavioral, mood and emotional responses.
Psychiatric illness can be divided in to neuroses and psychoses.
A neurotic patient usually retains sufficient insight to realize that he is ill. But the psychotic patient have difficulty understanding reality and their own conditions, they lives in a world of his own. They are often hallucinations and delusions (paranoid in nature), thought disorders and with drawel from social contacts and flattering of emotional responses.

The most important types of psychosis are
i) Schizophrenic :
It is neurological as well as psychological disorder. So fundamental and characteristic distortions of thinking and perception.
ii) Affective (mood) disorders :
Disorders in fundamental disturbance is a change in mood to depression associated by a change is the overall activity
iii) Organic psychosis :
Mental disturbances caused by head injuries, alcoholism, or other kind of organic diseases.

Classification :

1. Rauwolfia alkaloids : Reserpine, deserpidine
2. Phenothiazine derivatives : Chlorpromazine hydrochloride, Triflupromazine, Thioridazine hydrochloride, Mesoridazine hydrochloride, Piperacetazine hydrochloride,Prochlorperazine maleate, Trifluoperazine hydrochloride.
3. Ring analogues of phenothiazines :
   i) Thioxanthines – Chlorprothixene, thiothixene
   ii) Dibenzoxazepines – Loxapine succinate
   iii) Dibenzodiazepines – Clozapine
4. Butyrophenones : Haloperidol, Droperidol, Resoperidone
5. Diphenyl methane derivatives : Pipradrol, captodiame, Hydroxyzine, benactyzine
6. beta - Aminoketones : Molindone, Ondansetron
7. Benzamides : Sulperide, Remoxipride.
8. Miscellaneous : Buspirone, Meprobamate, Tybamate

Phenothiazine derivatives :

Synthesis of chlorpromazine:

Synthesis of prochlorperazine:

Ring analogues of phenothiazines :

1. Chlorprothxene

2. Thio thixene

3. Loxapine succinate SAR for Phenothiazine derivatives :

I. Modification in tricyclic systems :

1. Most of the compounds have either a six membered central ring (6-6-6)
   (Example : phenothiazine) classes for good antipsychotic activity.
   
2. Compounds having larger central ring Example : Imipramine (7 membered) and smaller central ring Example : carbazole (5 membered ring) are lack in antipsychotic activities and produce only antidepressant activity.
   
3. Analogues of tricyclic compounds that lock a central ring (Example :Rimozide) generally devoid of antipsychotic activity.

II. Modifications of alkyl side chain at R10 :

1. The maximum potency is obtained when the nitrogen of phenothiazine and basic amino group is connected by a three carbon side chain, because it permits maximum resemblance with that of most preferred conformational form of dopamine.
   
2. Introduction of methyl group at position 1, 2 or 3 of 3 – amines propyl side chain decrease the antipsychotic activity and may result Imipramine like activity.
   
3. If the side chain may be cyclopropane ring decrease neuroleptic activities and produce potent imipramine like activity.
   
4. If oxygen is introduced in to the 1st position of 3 – amino propyl chain results potent anti depressant activities (example : Chlorthiazine).
   
5. Bridging of position 3 of side chain to position 1 of phenothiazine nucleus reduces neuroleptic activity.

III. Modifications of basic amino group :

1. Maximum neuroleptic potency is obtained in amino alkyl substituents having 30 amines group than 20 and 10 amines group containing compounds.
   
2. Alkylation of basic amino group with groups larger than methyl group decreases neuroleptic potency. Example : Diethylamine analogues.
   
3. Replacement of dimethylamine group with Pyrrolidine, morpholine groups decreases the neuroleptic potency.
   
4. The activity is retained or increased if the amino group is replaced with piperidyl or Piperazine groups. Example : Mesoridazine, carphenazine.
   
5. Bridged piperidine derivatives retains the neuroleptic activities.
   
6. Introduction of hydroxyl , methyl, hydroxy ethyl groups of piperidine and Piperazine moieties increase the potency.
   
7. N4-Piperazine substituents with phenyl ethyl, p – amino phenyl ethyl or estirified long chain fatty acids increases the activity.

IV. Phenothiazine ring substituents at R2 :

1. Substituents at position 2 is optimal for neuroleptic potency, In general, potency increases in the following order of position of ring substitution 1<>
   
2. 2 – substitution is an electron withdrawing group increases the neuroleptic activity, the potency increases in the following order OH <>
   
3. Oxidation of sulfur at 5 – position decrease the neuroleptic activity.


4. 1,2,3,4 – Azo phenothiazines are more effective. 1-Azo phenothiazine is more potent than parent compound. Example: Prothioperdyl.

Butyrophenones :

1. Haloperidol

2. Droperidol 3. Risoperidone

SAR for Butyro phenone derivatives :

1. The 4- fluro phenyl group is necessary for optimal anti psychotic activity.


2. Reduction of carbonyl group and replacement of oxygen, sulphur or sulphone decreases the neuroleptic potency.


3. The bridge between benzoyl and amino group is propyl for good activity. If lengthening, shortening or branching the propylene chain of 4-amino Butyrophenones decreases neuroleptic potency.


4. The amino group is in tertiary form or part of six membered ring like piperidine, Piperazine for good neuroleptic activity.


5. Replacement of six membered ring by larger, smaller or uncyclized diminishes neuroleptic potency.


6. Neuroleptic potency is generally associated with 4,4- disubstituted piperidine. Substitution of 2 or 3 position of piperidine decreases potency

Mechanism of action

1. The neuronal activity in brain is mediated by neuro transmitter. Dopamine is a precursor of adrenaline and nor adrenaline and also function independently as a neurotransmitter. The dopamine have been found in thalamus, hypothalamus and basal ganglia and has depressant action.


2. The control of emotional responses, the hypothalamus is closely associated with reticular and limbic system which incorporates a balanced complex of excitatory(acetyl choline) and inhibitory (dopamine) components.


3. The psychoses associated with the presence of dopamine is greater than the normal level at central synopses in striatum and other brain regions.


4. The anti psychotic drugs act by increasing metabolic rate of dopamine or blocking dopamine (D2) receptors. This results an increasing concentration of excitatory (acetyl choline) and decreasing concentration of inhibitory (dopamine) components.


5. Since anti psychotic drugs shift the balance in favour of acetyl choline. Hence all the anti psychotic drugs are always associated with extra pyramidal effect.


6. The superimposibility of the conformations of dopamine ad phenothiazine derivatives blocks the dopamine receptors, because it possess 3 carbons in side chain separating two nitrogens.