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.