1. CNS DRUGS Chapter Objectives Different classes of CNS drugs
The mode of action of all these drugs
Critically analyze the differences in structural changes of all the classes of drugs and their antipsychotic, antidepressant or other activities
Analyze how the bulkiness of groups R1 and R2 affect the activity of the drugs against generalized seizures, partial seizures or absence seizures in the antiepileptic classes of drugs
The metabolic pathways and pharmacokinetics of the drugs indicated
Structures of most important drugs in the different classes of CNS drugs to recognize them from a group of structures as a specific class or its specific actions
The SAR in general and also for the individual drugs as indicated

2. Phenothiazines General Structure
Thioxanthenes
Phenothiazines
Ring with substituent is designated as “A” ring
More than 24 phenothiazine and the related thioxanthene derivatives are used in medicine, most of them for psychiatric conditions

3. Genesis
Development of phenothiazine-type antipsychotic drugs

4. Receptor Binding
Phenothiazines antipsychotic action is mainly through dopamine D2 receptor antagonistic activity

5. Dopamine Receptor
Since dopamine is structural analog of norepinephrine the receptor area is probably similarly configured, that is
Anionic site on receptor to interact with the protonated nitrogen of dopamine
A flat, hydrophobic area that interacts with the phenyl ring and hydrogen bonding at specific areas around the phenyl ring to accommodate the ring hydroxyls
A two carbon distance between the anionic site and the ring site

6. Kalani et al. PNAS March 16, 2004 vol. 101 no. 11 3819

7. Phenothiazine Binding to D2 Receptor
Protonatable nitrogen that can interact with the anionic site on the receptor
A phenyl ring to interact with the flat hydrophobic area of the receptor
The two carbon distance is attained through molecular bending of the side chain, which contains a three carbon bridge, toward one of the phenyl rings to approximate a two carbon distance
Ring geometry is also important in the binding of phenothiazines to their receptor

8. Ring Geometry

9. Antagonism vs Agonism
Phenothiazines interact with a variety of different receptors: Cholinergic, histaminergic, adrenergic, dopaminergic and serotonergic
All of these interact with their receptor in a similar mechanism which is basic nitrogen, hydrophobic area (an aromatic ring except for acetylcholine) and proper separation of the two functional groups. In addition there is some key hydrogen bonding that differs among the various species
In each case phenothiazines are antagonists and there are two possible reasons:
The bulk attached to the phenyl ring interferes with receptor perturbations resulting in an antagonistic effect rather than an agonistic effect
The g nitrogen may bind to the anionic site on the receptor but the bulky, hydrophobic ring structure may actually bind an allosteric site on the receptor effectively covering a portion of the receptor which would keep the agonist from binding

10. Allosteric site binding

11. SAR Ring substitutions
Electron withdrawing groups (X) enhance activity through two effects:
Pulls the electrons away from ring “A” resulting in a δ+ charge on the ring increasing binding of the ring to an electron rich area on the receptor which is another aromatic ring (induced dipole-induced dipole interaction – Charge Transfer)
Pulls the protonated nitrogen toward the phenyl ring providing the proper spacing between the nitrogen and the ring (two carbon distance)
To find the optimal position of X on the phenyl ring let’s examine the Chlorpromazine Index (CI). The CI is equal to the potency of the compound divided by chlorpromazine potency. CI greater than 1 indicates a compound more potent than chlorpromazine

12. The rank order of potency is position 2>3>4>1
Substituent
Ring A Position CI –H 2
0.4
–Cl
1.0 3
0.18 4
<0.08
–CF3
2.4
0.43
<0.06
–S–CF3
–OH 1
0.02
0.025
0.13
~0.4
–CH3
0.28
–(CH2)2CH3
–CHO
0.5
–COCH3
0.6
– COCH2CH3
2.0
– CO(CH2)2CH3
–SO2CH3
The most potent position for the electron withdrawing group is C2 which may help bending the side chain N through H bond to form dopamine-like conformation
The rank order of potency is position 2>3>4>1
Substitution at C1 has deleterious effect on antipsychotic activity (which may interfere the bending as in 1) as does (to a lesser extent) substitution at C4 which may interfere S binding to receptor like p-OH of dopamine does
Stronger electron withdrawers are more potent (exception may apply)
More than one substitution on the ring system decreases potency
Oxidizing the ring-sulfur to sulfoxide or sulfone reduces potency

13. Least potent
Most Potent

14. Alkyl Side Chain
Increasing or decreasing the length from 3 carbons decreases the potency. The further from 3 the less potent. Two carbon side chains increase H1 antagonism (Fenethazine)
Substitutions on the α carbon decrease potency
A methyl substituent on the β carbon can increase or decrease dopamine antagonism
A methyl substituent on the β carbon increases H1 antagonism. Substituents that are larger than methyl decrease antihistaminic activity unless they are part of a heterocycle (Methdilazine)
Substituents on the g carbon decrease dopamine antagonism but increase anticholinergic activity. These would be expected to produce less extrapyramidal side effects. All the piperidines fit this category
Fenethazine
Trimeprazine
Methdilazine
Thioridazine

15. Substituents on the g Nitrogen
There are three classes of phenothiazines based on the nature of this substituent
N,N-Dimethyl (aliphatic)
Piperazine
Piperidine
N,N dimethyl group is distinguished by dimethyl substitution on the g nitrogen. Names are ending by “–promazine” and the prefix depends on the C2 substituent. Their SAR are as follows:
Primary amines have low potency
Monomethyl compounds are better but still very weak
Dimethyl shows highest potency
Increasing carbon length, i.e. ethyl, decreases potency unless it is in a heterocycle in which case it has good potency (see piperazines and piperidines)
The order of potency based on g N substitution is: piperazine > aliphatic > piperidine

16. Piperazines are distinguished by incorporation of the g nitrogen into a piperazine ring. They are named as follows: If the para nitrogen has a methyl attached “–perazine”; If the para nitrogen has a hydroxyethyl attached “–phenazine”; The prefix depends on the C2 substituent. The SAR are as follows:
5 membered rings are more potent than 6 membered rings but no 5 membered ring drugs are on the market
A para nitrogen is better than no para nitrogen that is a piperazine is better than piperidine (attached at nitrogen or N1)
Rings with substituents are more potent than those without. Hydroxyethyl substituents are more potent than a methyl, which is better than nothing
Piperazine containing drugs are the most potent D2 antagonists of the phenothiazines
Fluphenazine

17. Piperidines are distinguished by incorporation of the g nitrogen into a piperidine ring. The phenothiazines using this derivative are 2-piperidines. A 1-piperidine would behave more like a piperazine. They are commonly named ending with “–ridazine”, the prefix comes from the C2 substituent. Their SAR follows the following pattern:
The g carbon branching lowers D2 affinity such that these have the lowest potency of the three classes of phenothiazines. However they are the most anticholinergic.
Thioridazine is a thioether, oxidation of the sulfur gives mesoridazine that retains activity
Thioridazine
Mesoridazine

18. Potency Comparison Potency at the D2 receptors:
Given equal C2 substituents, ranked from most potent to least potent - Piperazine > Aliphatic > Piperidine
Of drugs on the market, however, the rank is - Piperazine > Piperidine > Aliphatic
Anticholinergic potency: Piperidine > Aliphatic > Piperazine
α Receptor antagonism: Aliphatic > Piperidine > Piperazine (This may be due to the fact that in order to get a good antipsychotic effect (D2 antagonism) large doses must be given and so the α receptor antagonism, although weak, is seen more)
Extrapyramidal side effects: Piperazine > Aliphatic > Piperidine (Low anticholinergic potency in the presence of strong D2 block)
Sedation: Piperidine > Aliphatic > Piperazine

19. Metabolism of Phenothiazines
The phenothiazines are highly lipid soluble and present numerous functional groups that are susceptible to metabolism, most important are:
Ring hydroxylation possibly followed by glucuronidation, methylation or sulfation
S-oxidation
Dealkylation of the amine
Deamination

20. Hanche

21. Miscellaneous Antipsychotics
Butyrophenones
Thiothixene
Thioxanthenes

22. Butyrophenones (Butyro– 4 carbons, –Phen– phenyl, –one – ketone).
Thioxanthenes
N10 is replaced with a carbon. The α β carbon is a vinyl group (double bond) that introduces E, Z isomerism (cis, trans). Z (cis) toward position C2 is more potent (5-40x) which most marketed drugs are. All other SAR for phenothiazines would apply
Butyrophenones (Butyro– 4 carbons, –Phen– phenyl, –one – ketone).
In 3-D space the phenyl ring (Ar2) and the basic nitrogen approximate a two carbon distance. These compounds have High D2 potency with little anticholinergic effects. Optimal activity is seen when Ar1 & Ar2 are aromatic rings, a p-F in Ar1 aids activity; X = C=O; n = 3;N in alicyclic ring system. Y can vary, OH in haloperidol assist in activity 4
Haloperidol
Dibenzazepines (Dibenz– two benzene rings, –az– nitrogen, –epine 7 membered ring). SAR similar to phenothiazenes

23. Second Generation Antipsychotics
Loxapine
Clozapine
Clozapine and olanzapine are new generation atypical antipsychotics
Minimal extrapyramidal side effects and do not produce tardive dyskinesia
Beneficial in patients showing no response to classical neuroleptics (phenothiazines or butyrophenones)
Clozapine has relatively low affinity for brain dopamine D1 and D2 receptors (moderate affinity for D4) in comparison to its affinity at adrenergic a1 and a2, histamine H1, muscarinic M1 and serotonin 5-HT2A receptors
Olanzapine has somewhat different neurological profiles in that it is more potent antagonist at dopamine D2 and serotonin 5-HT2A receptors
Both are orally active and are metabolized by CYP3A4 (clozapine) or CYP1A2 (olanzapine) to inactive metabolites
Clozapine has half-life of 12 hours while olanzapine has a variable half-life of 20 to 50 hours
Quitiapine has similar brain receptor binding profile as clozapine. Loxapine has more typical neuroleptic biochemical profile with mainly antidopaminergic activity at D2-type receptors.

24. Benzisoxazoles/benziisothiazole
Resperidone is benzisoxazole and ziprasidone is the benzisothiazole containing antipsychotic agents
Risperidone is 5-HT2A/D2 antagonist with relatively high affinity at histamine H1 and adrenergic a1 and a2 receptors. It has less extrapyramidal side effects due to no dopamine inhibitory effect in striatum and cortex, well absorbed orally and metabolized by hepatic CYP2D6 to 9-hydroxy active metabolite with a half-life of 22 hours.
Ziprasidone is also 5-HT2A/C/D2 antagonist with relatively high affinity at histamine H1 and adrenergic a1 and a2 receptors. It can also activate 5-HT1A in brain and partial D2 agonist activity in some selective cells which are important for these atypical antipsychotics for little or no extrapyramidal effects. It has a half life of 6 hours with oral bioavailability ~60%

25. It is an arylpiperazine quinoline derivative with complex pharmacology
It is an arylpiperazine quinoline derivative with complex pharmacology. Dopamine D2 and serotonin 5-HT1A & 5-HT2A/C receptor inhibitions are believed to be involved in its antischizophrenic therapy. It has high affinity partial agonist effect to some D2 receptors depending on cell type, which explain its low extrapyramidal side effects.

26. New Molecular Entities in 2009
Asenapine is a new second generation antipsychotic (schizophrenia and manic episodes) for adults. It shows high affinity for numerous receptors, including serotonin, adrenergic, the dopamine, and histamine receptors; and much lower affinity for the mACh receptors as antagonist. Only sublingual dosage forms are available. Asenapine is reasonably absorbed with an absolute bioavailability of 35% for sublingual dosing - for oral dosing (i.e. the drug makes it into the stomach and bowel absorption) is far lower at ca. 2%. (This route of absorption also is really 'topical', even through the drug is orally dosed). Asenapine has high plasma protein binding (~95%), It is primarily metabolized by oxidative metabolism by CYP1A2 and also by direct glucoronidation by UGT1A4, and is cleared by both renal and hepatic routes in approximately similar proportions.
Iloperidone is a piperidinyl-benzisoxazole derivative atypical antipsychotic for the treatment of schizophrenia. The tertiary amine makes the molecule basic, but otherwise the molecule is largely lipophilic in character Blocks the sites of noradrenaline, dopamine, and serotonin receptors. In addition, pharmacogenomic studies identified SNPs associated with an enhanced response to iloperidone during acute treatment of schizophrenia.

27. Study Guide
What ring geometry favors antipsychotic and antidepressant activities and why?
Why phenothiazines are antagonists to dopamine receptro? Explain the binding modes.
What is the effect of ring substitution on antipsychotic potency? Know about both type and position of substitution.
What type of side chain favors the antipsychotic activity and antihistaminic activity? What is the effect on branching the side chain on both antihistaminic and antipsychotic effect?
What are different types of amine functions on the side chain? Compare their antipsychotic and othar effects of all three types of amines – the aliphatic, piperidine and piperazine.
What are thiothexenes and their activities? Activity difference of loxapine and amoxapine.
What are atypical antipsychotics? Why do they not possess extrapyramidal side effects?
Identify the atypical drugs from group of structures. How was ziprasidone developed?
Know all about iloperidone and asenapine