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

Phenothiazines General Structure

9

6

7

8N10

S5

1

2

3

4

X

ABC

N

R2

R1

Ring with substituent is designated as “A” ringMore than 24 phenothiazine and the related thioxanthene derivatives are

used in medicine, most of them for psychiatric conditions

S

N

R2

R1

X

Phenothiazines Thioxanthenes

GenesisO

O

CH2N(CH3)2

S NCH2CH2N(C2H5)2

S NCH2CHN(C2H5)2

CH3

O

CH2N(CH3)2

NCH2CH2N(CH3)2

H3CH2C

S NCH2CH2N(C2H5)2

Cl

CHOCH2CH2N(CH3)2

Benzodioxanes(antihistaminic)

Ethanolamines(antihistaminic)

Diphenhydramine(antihistaminic)

Ethylenediamines(antihistaminic)Diethazine

(anti-Parkinson)

Promethazine(antihistaminic)

Chlorpromazine(antipsychotic)

Development of phenothiazine-type antipsychotic drugs

Receptor Binding

H

H

N

HO

HO

Phenothiazines antipsychotic action is mainly through dopamine D2 receptor antagonistic activity

Dopamine Receptor

Since dopamine is structural analog of norepinephrine the receptor area is probably similarly configured, that is

1. Anionic site on receptor to interact with the protonated nitrogen of dopamine

2. 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

3. A two carbon distance between the anionic site and the ring site

OH

OH

+NH3

HH

HOH

Ser204

HO

Ser267

HO

NH2

Asn293O

Phe290

CO2-

Asp113

Fig.: Three-point interaction of pharmacophoric groups of NE with the receptor

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

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

Ring Geometry

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:

1. The bulk attached to the phenyl ring interferes with receptor perturbations resulting in an antagonistic effect rather than an agonistic effect

2. The 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

Allosteric site binding

SAR

Ring substitutions

9

6

7

8N10

S5

1

2

3

4

X

ABC

N

R2

R1 Electron withdrawing groups (X) enhance activity through two effects:

1. 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)

2. 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

Substituent Ring A Position CI

–H 2 0.4

–Cl 2 1.0

3 0.18

4 <0.08

–CF3 2 2.4

3 0.43

4 <0.06

–S–CF3 2 1.0

–OH 1 0.02

2 0.025

3 0.13

4 ~0.4

–CH3 2 0.28

–(CH2)2CH3 2 0.18

–CHO 2 0.5

–COCH3 2 0.6

– COCH2CH3 2 2.0

– CO(CH2)2CH3 2 2.0

–SO2CH3 2 0.6

1. 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

2. The rank order of potency is position 2>3>4>1

3. 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

4. Stronger electron withdrawers are more potent (exception may apply)

5. More than one substitution on the ring system decreases potency

6. Oxidizing the ring-sulfur to sulfoxide or sulfone reduces potency

O H O CH3 C O C O C OO S Cl S O S SS CF3OO S

NH3C CH3

H CH3 CH2

CH2

CH3

O

CH2

CH3

CH3 CH3 CH3 CH3 CF3 CF3

OO

Least potent Most Potent

Alkyl Side Chain

CH3

CH3

NN

S

Fenethazine

CH3

CH3CH3

NN

S

CH3NN

S

CH3S

CH3

NN

S

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 carbon decrease dopamine antagonism but increase anticholinergic activity. These would be expected to produce less extrapyramidal side effects. All the piperidines fit this category

Trimeprazine

Methdilazine

Thioridazine

Substituents on the Nitrogen

There are three classes of phenothiazines based on the nature of this substituent

1. N,N dimethyl group is distinguished by dimethyl substitution on the nitrogen. Names are ending by “–promazine” and the prefix depends on the C2 substituent. Their SAR are as follows:

a) Primary amines have low potency

b) Monomethyl compounds are better but still very weak

c) Dimethyl shows highest potency

d) 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)

e) The order of potency based on N substitution is: piperazine > aliphatic > piperidine

1. N,N-Dimethyl (aliphatic)2. Piperazine3. Piperidine

HN

NH

OHN

CF3

NN

S

2. Piperazines are distinguished by incorporation of the 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:

a) 5 membered rings are more potent than 6 membered rings but no 5 membered ring drugs are on the market

b) A para nitrogen is better than no para nitrogen that is a piperazine is better than piperidine (attached at nitrogen or N1)

c) Rings with substituents are more potent than those without. Hydroxyethyl substituents are more potent than a methyl, which is better than nothing

d) Piperazine containing drugs are the most potent D2 antagonists of the phenothiazines Fluphenazine

HN3. Piperidines are distinguished by incorporation

of the 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:

a) The carbon branching lowers D2 affinity such that these have the lowest potency of the three classes of phenothiazines. However they are the most anticholinergic.

b) Thioridazine is a thioether, oxidation of the sulfur gives mesoridazine that retains activity

CH3S

CH3

NN

S

Thioridazine

O

CH3S

CH3

NN

S

Mesoridazine

Potency Comparison

Potency at the D2 receptors:

a) Given equal C2 substituents, ranked from most potent to least potent - Piperazine > Aliphatic > Piperidine

b) 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

The phenothiazines are highly lipid soluble and present numerous functional groups that are susceptible to metabolism, most important are:

1. Ring hydroxylation possibly followed by glucuronidation, methylation or sulfation

2. S-oxidation

3. Dealkylation of the amine

4. Deamination

Metabolism of Phenothiazines

Miscellaneous AntipsychoticsS

N

R2

R1

XAr1X(H2C)n N

Ar2

Y

Thioxanthenes

CH3

N

OO

CH3

CH3

NS

N

S

ButyrophenonesThiothixene

ThioxanthenesN10 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

S

N

R2

R1

X

Ar1X(H2C)n NAr2

Y4

Dibenzazepines (Dibenz– two benzene rings, –az– nitrogen, –epine 7 membered ring). SAR similar to phenothiazenes

F

O

N

OH

Cl

Haloperidol

H3C

S

NNH

CH3

N

N

Olanzapine

OHO

NS

N

N

Quetiapine

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 1 and 2, 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.

Cl

NO

CH3N

N

Cl

NNH

CH3

N

N

Loxapine Clozapine

Second Generation Antipsychotics

Benzisoxazoles/benziisothiazole

Ziprasidone

F

N

N

O

H3C

N

O N RisperidoneHN

O

Cl

N

N

SN

HCl

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 1 and 2 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 1 and 2 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%

Cl

Cl

N

NO O

HN

Aripiprazole

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.

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.

N O

OCH3

CH3

O

ON

F ILOPERIDONE Fanapt

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.

Cl

O N CH3

ASENAPINE Saphris

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