1. th Lecture Medicinal Chemistry
Antipsychotics
th Lecture Medicinal Chemistry
Douglas L. Geenens, D.O. 2000

4. Douglas L. Geenens, D.O. 2000

5. Douglas L. Geenens, D.O. 2000

6. Physiology of dopamine
Nigro srtiatal projection:
Spontaneitiy, switching
Intended actions
Motor learning, habit learning
Egocentric representation of the body in space
Mesolimbic projection
Reward prediction
Approach, appetence
Part of the brain reward system

7. Enhanced activity in the mesolimbic projection
Enhanced DA activity in the nigrostriatal projection
Hyperactivity
Hyperkinesia
Enhanced activity in the mesolimbic projection
Enhanced appetence
Drive
Addiction
Schizophrenia

8. Pathophysilogy of dopamine (DA)
Reduced DA activity in the nigro striatal projection
Bradykinesia, swiching deficit (motor and cognitive)
Akinesia, Rigor, Tremor (Symptoms of Parkinson‘s disease)
Deficits in implicit learning
Reduced DA activity in the mesolimbic projection
Reduced appetence, drive
Reduced activity of the brain reward system

9. Mesolimbic pathway
Hyperactivity on this pathway is associated with positive symptoms of schizophrenia
Mesocortical pathway
Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia

10. Symptoms are:
Positive symptoms: Hallucinations, delusions (Increase in mesolimbic dopamine causes positive symptoms of schizophrenia).
Negative symptoms: apathy, social withdrawal, and anhedonia (Deficit in mesocortical dopamine causes negative and cognitive deficits of schizophrenia).
Douglas L. Geenens, D.O. 2000

11. Nigrostriatal pathway
Part of extrapyramidal system and controls motor movement
Blockade of D2 receptors causes:
-- deficiency in dopamine in this pathway and thus movement disorder such as Parkinson’s disease
-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway
Increased neuronal activity of this pathway inhibits prolactin release
Blockade of D2 receptor increases prolactin release and causes:galactorrhea,amenorrhea

12. Dopamine Hypothesis
All known antipsychotics drugs are capable of treating positive psychotic symptoms by blocking the dopamine receptors, especially D2 receptors

13. Dopamine Pathways Nigrostriatal
Projects from the substania nigra to the basal ganglia
A part of the extrapyramidal system
Thus side effects are called “extrapyramidal” = Dystonias, Akathisia and Pseudoparkinsonism
Dopamine Pathways Nigrostriatal

14. Dopamine Pathways Nigrostriatal
Controls movements
The term “neuroleptics” refers to:
Antipsychotics ability to “quiet the neurological system”
To their neurological side effects

15. Dopamine Pathways Nigrostriatal
Types of movement disorders caused by this pathway include:
Akathisia “Decreased muscular movements”
Dystonia “Uncoordinated spastic movements of muscle groups: Trunk, tongue, face”
Tremor, rigidity, bradykinesia

16. Dopamine Pathways Nigrostriatal
Chronic blockade can cause:
Potentially irreversible movements around the buccal-lingual-oral area: “Tardive Dyskinesia” associated with long-term use of antipsychotics (chronic dopamine blockade)

17. Dopamine Pathways Mesocortical
Associated with both positive and negative symptoms
Blockade may help reduce negative symptoms of schizophrenia
Involved in the cognitive side effects of antipsychotics “mind dulling”
Douglas L. Geenens, D.O. 2000

18. Dopamine Pathways Tuberoinfundibular
Blockade produces galactorrhea
Blockade produces amenorrhea

19. Dopamine Pathways Summary
Blocking dopamine receptors in only one of them is useful (mesolimbic).
Blocking dopamine receptors in the other three are harmful.

20. Antipsychotics Are Use in the treatment of psychoses “schizophrenia”
• Imbalance of neurotransmitters: Dopamine, serotonin, glutamate.
Positive symptoms: Hallucinations, delusions (Increase in mesolimbic dopamine causes positive symptoms of schizophrenia).
Negative symptoms: apathy, social withdrawal, and anhedonia (Deficit in mesocortical dopamine causes negative and cognitive deficits of schizophrenia).
Douglas L. Geenens, D.O. 2000

21. Uses of these agents are in manic disorders and the schizophrenias
Uses of these agents are in manic disorders and the schizophrenias. In the manic disorders, the agents may block DA at limbic D2 and D3 receptors, reducing euphoria, delusional thinking, and hyperactivity.
In the chronic idiopathic psychoses (schizophrenias), both conventional (typical) and newer (most are atypical) antipsychotics appear to act to benefit positive symptoms by blocking DA at D2 and D3 limbic receptors.
The bases of the atypical group's activity against negative symptoms may be serotonin-2A receptor (5-HT2A) block.

22. Typical or Conventional or traditional First Generation Antipsychotics

23. Substitution at the 3 position with EWG can
improve activity when its not substituted at 2
Activity
increases
as electron
withdrawing
ability of the
substituent
Increases or
presence of
atom with
unshared pair
of electron
Substitution at position 1
has a deleterious effect
on antipsychotic activity,
as does (to a lesser extent)
substitution at the 4 position

24. Phenothiazine SAR
Propyl Side Chain
Propyl is best, butyl is nearly inactive, ethyl has low activity. Compounds with ethyl chains often have antihistaminic activity.
Any substituent at the first position of the side chain decreases activity.
Substitution of a methyl at position 2 of the chain is OK but levo is more active than dextro.
A larger range of substitutions are tolerated at position 3. The nitrogen is often included as part of a ring.

25. 2. Modification of the Tricyclic Nucleus
Phenothiazine SAR
2. Modification of the Tricyclic Nucleus
Replacing S with C, O, Se, etc. decreases activity.
Replacing the nitrogen eliminates activity, however, can be replaced by bio-isosteric olefin (see thioxanthene).

26. Phenothiazine SAR
3. Modification of X
Highest activity is associated with an electron withdrawing, lipophilic substituent (halogen) at position 2. A trend in activity changes can be seen with alterations in the identity of X; increasing lipophilicity and e- withdrawing increases activity.
Disubstitution of the ring decreases activity, ring cleavage is inactivating.

27. 4. Modification of Side Chain Amino Group
The highest activity is for 3°amines.
Methyl groups on nitrogen have greater activity than larger aliphatic groups.
The amino group can be part of a cyclic structure. The cyclic amines include pyrrolidine, piperidine, and piperazine. The piperazine substituent, in particular, generally increases potency.
Propyl dimethylamino side chain
(chlorpromazine)
propyl piperdinyl and pyrrolidinyl side chain
(thioridazine)
Propyl piperazine side chain
(prochlorperazine)

28. Phenothiazine Metabolism
Three major processes; all give compounds that are less active:
1. Ring hydroxylation at 7 position (active metabolite) – followed by glucuronidation
2. N-dealkylation at both nitrogen.
3. Oxidation at S (inactive metabolite).

29. Douglas L. Geenens, D.O. 2000

30. Chlorpromazine Hydrochloride
Was the first phenothiazine compound introduced into therapy.
It is still useful as an antipsychotic.
Other uses are in nausea, vomiting and hiccough.
It is the reference compound in activity comparisons. The drug has significant sedative and hypotensive properties, reflecting central and peripheral α1-noradrenergic blocking activity, respectively.
Effects of peripheral anticholinergic activity are common. As with the other phenothiazines, the effects of other CNS-depressant drugs, such as sedatives and anesthetics can be potentiated.

31. Promazine
As it is not substituted in position 2 by Cl a milligram potency decreases as an antipsychotic. Tendency to EPS is also lessened, which may be significant, especially if it is decreased less than antipsychotic potency.

32. Triflupromazine Hydrochloride
Has lower sedative and hypotensive effects than chlorpromazine and greater milligram potency as an antipsychotic. EPS are higher. The 2-CF3 versus the 2-CI is associated with these changes. Overall, the drug has uses analogous to those of chlorpromazine.

33. Thioridazine Hydrochloride
Mellaril is a member of the piperidine subgroup of the phenothiazines.
The drug has a relatively low tendency to produce EPS (high anticholinergic activity in the striatum, counterbalancing a striatal DA block, and increased DA receptor selectivity).
The drug has sedative and hypotensive activity in common with chlorpromazine and less antiemetic activity.
At high doses, pigmentary retinopathy has been observed.

34. Mesoridazine Besylate
It is the active metabolite of the thioridazine, shares many properties with thioridazine. No pigmentary retinopathy has been reported.

35. Ring Analogs of Phenothiazines: Thioxanthenes, Dibenzoxazepines, and Dibenzodiazepines
The ring analogs of phenothiazines are structural relatives of the phenothiazine antipsychotics.
Most of them share many clinical properties with the phenothiazines.

36. Thiothixene
The thioxanthene system differs from the phenothiazine system by replacement of the N-H moiety with a carbon atom doubly bonded to the propylidene side chain.
With the substituent in the 2 position, Z (cis) and E (trans) isomers are produced.
In accordance with the concept that the presently useful antipsychotics can be superimposed on DA, the Z (cis) isomers are the more active antipsychotic isomers.
The compounds of the group are very similar in pharmacological properties to the piperazine subgroup of the phenothiazines. Thus, thiothixene displays similar properties.

37. Fluorobutyrophenones
Optimal activity is seen when AR1 is an aromatic system.
p-fluoro substituent aids activity.
When X = C=O, optimal activity is seen, although other groups, C(H)OH and C(H)aryl (diarylbutylpiperidine: PIMOZIDE), also give good activity.
When n = 3, activity is optimal; longer or shorter chains decrease activity.
The aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form.
AR2 is an aromatic ring and is needed. It should be attached directly to the 4 position or (occasionally) separated from it by one intervening atom.
The Y group can vary and assist activity. An example is the hydroxyl group of haloperidol.

38. Haloperidol is a potent antipsychotic useful in schizophrenia and in psychoses associated with brain damage. It is frequently chosen as the agent to terminate mania.
Droperidol may be used alone as a pre-anesthetic neuroleptic or as an antiemetic. Its most frequent use is in combination with the narcotic agent fentanyl pre-anesthetically.

39. Atypical or 2nd generation agents
Douglas L. Geenens, D.O. 2000

40. Atypical or 2nd generation agents
Relieve both positive and negative symptoms of psychosis
Block both dopamine and serotonin receptors
Cause less movement disorders
Examples: clozapine and risperidone

41. Ring Analogs of Phenothiazines: Dibenzoxazepines, and Dibenzodiazepines
The dibenzodiazepine clozapine is an important atypical antipsychotic as it has important differences:
Low production of EPS.
Reduction of negative symptoms.

42. A dibenzoxazepine derivative in use is loxapine succinate
A dibenzoxazepine derivative in use is loxapine succinate. It is an effective antipsychotic and has side effects similar to those reported for the phenothiazines. The dibenzodiazepine derivative is clozapine. It is not a potent antipsychotic on a milligram basis (note the orientation of the N-methyl piperazino group relative to the chlorine atom). It is effective against both positive and negative symptoms of schizophrenia and has a low tendency to produce EPS. There are legal restrictions on its use because of a relatively high frequency of agranulocytosis.

43. Olanzapine (dibenzodiazepine) and Quetiapine (dibenzothiazepine) possess tricyclic systems with greater electron density than chlorpromazine. They thus resemble clozapine. The drugs are atypical antipsychotics.

44. Olanzapine and Quetiapine
Overall, these two compounds should bind less strongly to D2 receptors and permit more receptor selectivity among receptor subtypes than typical antipsychotics.
This could account for decreased striatal D2-blocking activity, which would produce less discomfort in patients.

45. Benzisoxazole: Risperidone
It is an important atypical antipsychotic with the structural features of a hybrid molecule between a butyrophenone antipsychotic and a trazodone-like antidepressant.
It benefited refractory psychotic patients, with parkinsonism controlled at one-tenth the dose of antiparkinsonian drugs used with haloperidol. coexisting anxiety and depressive syndromes were also lessened.

46. Decrease negative and positive symptoms of schizophrenia due to
blocking
5-HT2-D2
receptor.
Risperidone
Douglas L. Geenens, D.O. 2000

47. Dihydroindolones
They evolved out of research on the alkaloid lobeline.
The overall structural features associated with activity can be seen in the structure of molindone
In addition to the ß-aminoketone group, there must be an aryl group positioned as in molindone.
Douglas L. Geenens, D.O. 2000

48. It is about as potent an antipsychotic as trifluoperazine.
It might be conjectured that the proton on the protonated amino group in these compounds H-bonds with the electrons of the carbonyl oxygen atom.
This would produce a cationic center, two-atom distance, and an aryl group that could be superimposed on the analogous features of protonated dopamine.
It is about as potent an antipsychotic as trifluoperazine.
Overall, side effects resemble those of the phenothiazines.
Douglas L. Geenens, D.O. 2000

49. Benzamides
The benzamides evolved from observations that the gastro­prokinetic and antiemetic agent metoclopramide has antipsychotic activity related to D2 receptor block. It was hoped that the group might yield compounds with diminished EPS liability.
Douglas L. Geenens, D.O. 2000

50. This expectation appears to have been met
This expectation appears to have been met. An H-bond between the amido H and the unshared electrons of the methoxy group to generate a pseudo ring is considered important for antipsychotic activity in these compounds. Presumably, when the protonated amine is superimposed on that of protonated dopamine, this pseudo ring would superimpose on dopamine's aromatic ring. These features can be seen in sulpiride and remoxipride.
Douglas L. Geenens, D.O. 2000

51. Antimanic Agents
LITHIUM SALTS

52. Antipsychotics are used in manic disorders
Antipsychotics are used in manic disorders. In the manic disorders, the agents may block DA at limbic D2 and D3 receptors, reducing euphoria, delusional thinking, and hyperactivity.

53. Salts of Lithium
The lithium salts used are the carbonate (tetrahydrate) and the citrate.
Lithium chloride: is not used because of its hygroscopic nature and because it is more irritating than the carbonate or citrate to the GI tract.

54. Mechanism of Action
The active species in these salts is the lithium ion.
The classic explanation for its antimanic activity is that it resembles the sodium ion and can occupy the sodium pump.
Unlike the sodium ion, it cannot maintain membrane potentials.
Accordingly, it might prevent excessive release of neurotransmitters (dopamine) that characterize the manic state.

55. Indications
The indications for lithium salts are:
1. Acute mania (often with a potent neuroleptic agent for immediate control, since lithium is slow to take effect).
2. As a prophylactic to prevent occurrence of the mania of bipolar manic-depressive illness

56. Because of its water solubility, the lithium ion is extensively distributed in body water.
It tends to become involved in the many physiological processes involving Na, K, Ca and Mg ions, hence, many side effects and potential drug interactions exist.
The margin of safety is low; therefore lithium should be used only when plasma levels can be monitored routinely.
In the desired dose range, side effects can be adequately controlled.

57. In the future:
Because of the toxicity of lithium, there is substantial interest in design of safer compounds.
As more is learned about lithium's specific actions, the likelihood of successful design of compounds designed to act on specific targets is increased.
Actually, carbamazepine and valproic acid (target sodium channels) are proving to be effective.

58. Thanks for your attention