1. Welcome
CNS Stimulants 2
Dr. Dana Ameen

2. References
Wilson and Gisvold's Organic Medicinal and Pharmaceutical Chemistry
Foye’s Principles of Medicinal Chemistry
Medicinal Chemistry by Ashutosh Kar

3. Neuronal Synapse - NE Mechanism
Goodman and Gilman, 9th Edition

4. MONOAMINE OXIDASE INHIBITORS
Inhibit liver MAOs in addition to brain MAOs, thereby allowing dietary pressor amines that normally would be inactivated to exert their effects.
A number of severe hypertensive responses, sometimes fatal, have followed ingestion of foods high in pressor amines.

5. Foods (rich in tyramine) to Avoid
ALCOHOLIC BEVERAGES
BEAN
CHEESE
FISH
GINSENG
PROTEIN EXTRACTS
MEAT
SAUSAGE, BOLOGNA, PEPPERONI and SALAMI
SOUPS

6. Side effects Inhibit liver MAOs in addition to brain MAOs.
Another prominent side effect of the MAOI is orthostatic hypotension.
Some of them produce serious hepatotoxicity.

7. 1. Non selective MAO A and B inhibitors: A
1. Non selective MAO A and B inhibitors: A. Hydrazines: Isocarboxazid Isoniazid Nialamide Procarbazine Hydracarbazine B. Non Hydrazines: Tranylcypromine

8. 2. Selective MAO inhibitors
A. Selective MAO A inhibitors:
Moclobemide (reversible)
Pirindole
Toloxatone
B. Selective MAO B inhibitors:
Rasagiline
Selegeline

9. They are converted by MAO to agents that inhibit the enzyme irreversibly.
Moclobemide is a reversible inhibitor of MAO-A, it is considered to be an effective antidepressant and permits dietary tyramine to be metabolized.

10. Phenelzine Sulfate, USP
2-(phenylethyl) hydrazine sulfate
After oxidation to diazine, which then break up into molecular nitrogen, a hydrogen atom, and a Phenylethyl free radical.
The latter would be the active species in irreversible inhibition

11. Tranylcypromine
One electron of the nitrogen pair lost to flavin →produces homolytic fission of a carbon-carbon bond of cyclopropane, one electron from the fission pairing with the remaining lone nitrogen electron to generate an protonated imine (C6H6CHCH2C=NH+.2), the other residing on a methylene carbon.
Thus, a free radical (C6H6CHCH2C=NH+.2) is formed to inactivate the enzyme.

12. Tricyclic Antidepressant Compounds (and Mechanistically Related)
Almost all of the original agents block neuronal reuptake of NE, 5-HT, and DA.
As with the MAOIs, there is a time lag before antidepressant effect which is due:
Desensitization of receptors (α2, β and 5-HT2).
They are extremely lipophilic and, accordingly, highly tissue-bound outside the CNS.

13. Neuronal Synapse - NE Mechanism
Goodman and Gilman, 9th Edition

14. The SARs for the TCAs
A large, bulky group encompassing two aromatic rings, preferably held in a skewed arrangement by a third central ring and a three- or sometimes two-atom chain to an aliphatic amino group that is mono methyl- or dimethyl­ substituted.
Fully extended trans conformation of the β–aryl amines.
The dimethylamino compounds tend to be sedative.
The mono-methyl relatives tend to be stimulatory.

16. PRODUCTS Imipramine Hydrochloride (Tofranil®)
As is typical of dimethylamino compounds, anticholinergic and sedative effects tend to be marked.
Metabolic inactivation proceeds mainly by oxidative hydroxylation in the 2-position, followed by conjugation with glucuronic acid.

17. Clomipramine 50 times as potent as imipramine:
1. Increased distribution to the brain.
2. Cl-H bonding to help stabilize β-aryl amine-like conformations.

18. Amitriptyline Hydrochloride
It is one of the most anticholinergic and sedative TCAs, because it lacks the ring electron-enriching nitrogen atom.
Metabolic inactivation mainly proceeds at the benzylic 10-position. Conjugation produces excretable metabolites.
By N-demethylation nortriptyline is produced, which has a less anticholinergic, less sedative, and more stimulant action than amitriptyline.

19. Maprotiline Hydrochloride
Ludiomil® is described as a tetracyclic antidepressant. The description is chemically accurate.
It can be viewed as a TCA with an ethylene-bridged central ring.
The compound has been noted to have stimulant properties.

20. Amoxapine
It has significant effects at D2 receptors. The N-methyl-substituted relative is the antipsychotic loxapine.
It is reported that the 8-hydroxy metabolite of amoxapine is also active as an antidepressant.

22. Trazodone Hydrochloride
It has similarities with the fluorobutyrophenone, whereas the fluorobutyrophenone antipsychotic block DA postsynaptically, trazodone as well as its major metabolite m-chloro-4-phenylpiperazine block presynaptic uptake of 5-HT.

23. Serotonin Reuptake Inhibitors
Fluoxetine
Paroxetine
Sertraline
Fluvoxamine
Serotonin reuptake inhibitors have received much favorable attention as an antidepressant.
They look like the protonated amino group, H-bonding to the ether oxygen to generate the β-aryl amino-like group with the bulge on the side.

24. The SSRI paroxetine seems to conform to the general structural feature of the group, as do the SSRIs sertraline and fluvoxamine. Fluvoxamine is used especially in OCD.

25. Selective Serotonin Reuptake Inhibitors SSRI
Citalopram
Escitalopram is the (S)-stereoisomer (Left-enantiomer) of citalopram.

26. PSYCHEDELICS
Are agents which produce 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 psychotomimetics.

27. PSYCHEDELICS 1. INDOLETHYLAMINES: Dimethyltryptamine
Psilocybin and Psilocyn
2. PHENYLETHYLAMINES:
Mescaline, DOM and MDA.
3. Agents possessing both an indolethylamine and a phenylethylamine moiety:
(+)-Lysergic Acid Diethylamide (LSD)

28. ( + )-Lysergic Acid Diethylamide (LSD)
The stereochemistry is important. Chirality as shown must be maintained or activity is lost; likewise, the location of the double bond as shown is required. LSD has marked effects on serotoninergic neurons.

29. DISSOCIATIVE AGENTS
Phencyclidine was introduced as a dissociative anesthetic for animals. It’s a close structural relative to ketamine. The drug produces a sense of intoxication: there are hallucinogenic experiences, but unlike those produced by the anticholinergic hallucinogens and often amnesia.
The drug affects many systems, including those of NE and 5-HT. It reportedly blocks glutaminergic N-methyl-D-aspartate receptors. This probably is the basis for many of its CNS effects.

30. EUPHORIANT-STIMULANT
Cocaine as a euphoriant-stimulant psychotomimetic, and drug of abuse amphetamine, with which it shares many biologic properties.
At low doses, it produces feelings of well-being, decreased fatigue, and increased alertness.

31. DEPRESSANT-INTOXICANT Δ9-or Δ1-tetrahydrocannabinol THC
Is a depressant with stimulant sensations arising from depression of higher centers.
Pleasant effects → low doses.
Higher doses → psychotomimetic actions (dysphoria, hallucinations and paranoia).
SARs (the phenolic OH is required for activity) for cannabinoids suggest action at receptors (2).

32. Thanks
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