cns stimulants & antidepressants central nervous system

CNS stimulants & Antidepressants

1 of 41

Central Nervous System Stimulants

Drugs that produce stimulation of the central nervous system could be classified into the following categories: 1- Analeptics: This is a group of agents with a very limited range of use (mainly as respiratory stimulants) because of the general nature of their effects. The methylxanthines have interesting stimulant properties. 2- Central sympathominetics: Amphetamine and closed relatives, have alerting and antidepressant properties, but are now used as anorexients. 3- Antidepressants drugs: these are the most frequently employed in serious depressive disorders and broadly groupable into: a- Non-selective (Norepinephrine-Serotonin) reuptake inhibitors b- Selective noradrenaline reuptake inhibitors c- Selective serotonin reuptake inhibitors d- Dopamine and noradrenaline reuptake inhibitors e- 5-HT2 and 5-HT3 blockers (antagonists) f- MAO inhibitors 4- Psychedelic drugs: These drugs have broad range of CNS effects including CNS stimulation.

Analeptics

Methylxanthines Caffeine, theophylline and theobromine are the members of this group. They are psychomotor stimulants. The CNS stimulant action is related to the ability of these compounds to antagonize adenosine A receptors. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine. These compounds are usually dispensed in a variety of mixtures or complexes to increase solubility in water as citrated caffeine, caffeine sodium benzoate, theophyline ethylenediamine (Aminophylline).Caffeine is used in the treatment of migrain. adenosine A receptors. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine.


2 of 41

HO

HO

OH

O

N

N

NH2

N

N

Adenosine These compounds are usually dispensed in a variety of mixtures or complexes to increase solubility in water as citrated caffeine, caffeine sodium benzoate, theophyline ethylenediamine (Aminophylline).Caffeine is used in the treatment of migrain. - All xanthines stimulate pepsin secretion, so they are contraindicated in peptic ulcer.

The relative pharmacological properties of the xanthines are shown in the following table

Structure CNS, Respiratory, and

Skeletal Muscle Stimulation

Cardiac Stimulation, Coronary Diltation, Smooth Muscle Relaxation

and Diuretics

1 3

2 1

Caffeine

N

N N

N

O

O

N

N N

N

O

O

H

Theophylline


3 of 41

3 2

Central Sympathomimetic Agents (Psychomotor Stimulants) Amphetamine and related drugs

As discussed under sympathetic drugs, that the group of indirect sympathetic agonist where obtained by certain structure modification of NE that lead to production of compounds more resistant to metabolism and better able to crosss the blood-brain barrier. These effects increase the proportion of central to peripheral activity and sometimes referred as central sympathomimetic agents. Their central activity is manifested as excitation, wakefulness, in addition to anorexient effects. Dopaminergic and serotoninergic effects are also operative. Structure Activity Relationship of Central Sympathomimetic Drugs They are �-phenethylamine derivatives. Amphetamine is the prototype of this group. It is concidered as phenylisopropylamine derivative: 1- �–phenethylamine, a constituent of cheese and chocolate, is without central activity due to facile metabolic inactivation by MAO which degrades the amphetamines and neurotransmitters they release.

N

N N

N

O

O

H

Theobromine

NH2

Phenethylamine

NH2

Amphetamine, has increased CNS rather than prepheral activity, presumably by retarding metabolismNo CNS effect


4 of 41

2- Branching with lower alkyl groups on the �-carbon increases CNS rather than peripheral activity, presumably by retarding metabolism. 3- The �-branching generates chiral center and stereoselectivity of possible enantiomers is apparent. The dextro (S-isomer) of amphetamine is up to 10 times as potent as the levo (R-isomer) in alerting activity and about twice as active as psychomimetic agent. 4- Hydroxylation of the �-carbon or the aromatic ring decreases activity, as the result of decreasing ability to cross the blood-brain barrier. For example, phenylpropanolamine (Norephedrine) has about 1/100th the ability to cross the blood-brain barrier of its deoxy congener, amphetamine.

(Norephedrine) 5- Halogenation (F, Cl, Br) of the aromatic ring decreases sympathomimetic activity. Other activities may increase. p-Chloroamphetamine has strong central sertoninergic activity . 6- Methoxyl substitution on the ring tends to produce psychomimetic agents, suggesting trophism for dopaminergic (D2) receptors. 7- N-Methylation increases activity. Di-N-methylation decreases activity. Mono-N-substituents larger than methyl decrease excitatory properties, but many compounds retain anorexient properties. So, compound of this type are useful anorexients with decreased abuse potential relative to amphetamine.

NH2

NH2NH2

CH3HH3CH

S(+) Dextroamphetaminemore potent than R isomer

R(-) Levooamphetamine

Amphetamine

NH2

OH

β− hydroxyamphetamine


5 of 41

- The abuse potential of the more euphoriant and stimulatory of the amphetamines and amphetamine like drugs, such as cocaine is well documented and they produce an exceedingly destructive addiction. The major medical uses of these type of drugs include narcolepsy, Parkinson's disease, attention deficit disorders and although not the preferred agents, as anorexients.

Mechanism of Action of Amphetamines These compounds and certain of their metabolites which have resemblance to NE can have complex and multiple actions and can participate in the various neuronal and postsynaptic processes involving NE such as synthesis, release, uptake and pre-and postsynaptic receptor activation. They are indirect-acting dopaminergic and noradrenergic agents. Increase Dopamine and Noradrenaline levels in synapse. The central stimulant effects involve the dopamine system. Enhance the release of dopamine and to a lesser extent, prevents its reuptake into presynaptic terminals.

Members of Central Sympathomimetic Drugs Amphetamine Sulfate (Benzedrine) �-Methylbenzene ethanamine (±)-1-Phenyl-2-aminopropane - The racemic mixture has a higher properties of cardiovascular effects than the dextro-isomer. For most medical uses, the dextro-isomer is preferred.

Dextroamphetamine Sulfate Dextroamphetamine with (S) configuration has less cardiovascular effects than the levo R-isomer. It is also 10 times as potent as an alerting agent and twice as potent as psychomimetic agent.

NH2

Amphetamine


6 of 41

The �-methyl group retards but not terminates, metabolism by MAO. It is metabolized by oxidative deamination to phenylacetone and ammonia. Phenylacetone is further metabolized to benzoic acid Metabolism of amphetamine

Methamphetamine hydrochloride (+ ),N,� -dimethylphenethylamine hydrochloride

Methamphetamine is the N-methylanalogue of dextroamphetamine. It has more central activity and more abuse potentail. Methamphetamine is an addictive stimulant drug that strongly activates certain systems in the brain. Methamphetamine is chemically related to amphetamine, but the central nervous system effects of methamphetamine are greater. Both drugs have some limited therapeutic uses, primarily in the treatment of obesity. Methamphetamine is made in illegal laboratories and has a high potential for abuse and addiction. Street methamphetamine is referred to by many names, such as "speed," "meth," and "chalk." Methamphetamine hydrochloride, clear chunky crystals resembling ice, which can be inhaled by smoking, is referred to as "ice," "crystal," "glass," and "tina."

Chlorphentermine hydrochloride

NH2

Amphetamine

NH2

OH

NHOH

O

O

OH

COOHNH2

HO

α− Hydroxyamphetamine

N-Hydroxyamphetamine

Phenylacetone

p-Hydroxyamphetamine Benzoic acid Hydroxy keto derivative

NHCH3


7 of 41

p-Chloro-�.,�.-dimethylphenethylamine hydrochloride.

Chlorphentermine has strong serotonergic activity and is an effective anorexient with less abuse potential than dextroamphetamine.

Fenfluramine Hydrochloride (Pondrimin) N-Ethyl-(�-methyl-m-(trif1uoromethyl)phenylethylamine hydrochloride

Fenf1uramine is unique in producing sedation rather than excitation principally by central serotoninergic rather than noradrenergic mechanism. It is selective and long acting 5-HT depleting agent. The drug is favored in patients in whom CNS stimulation is to be avoided, and in weight reduction in non-insulin-dependent diabetes mellitis.

Methylphenidate Hydrochloride (Ritalin) � -Phenyl-2-piperidine acetic acid methyl ester Methylphenidate has two chiral centers and have four possible isomers. The threo-racemate is about 400 times as potent as erythro-racemate and it is the marketed compound.

Cl

NH2

NH

CF3

COOCH3

HN

Retalin;methylphenidate


8 of 41

COOCH3

HN

Retalin;methylphenidate

COOCH3

HN

p-Hydroxy metaboliteActive

COOH

HN

Retanilic acidInactive

HO

Methylphenidate or its p-hydroxy metabolite, or both: - blocks NE uptake - acts as a post-synaptic agonist - depletes the stored NE pool as reserpine - blocks of DA reuptake. Methylphenidate is a potent CNS stimulant indicated in cases as narcolepsy and the attention deficit disorders. The compound is metabolized (80-90%) also by esterases to inactive ritalinic acid. Khat or kat Khat is used for its central stimulant action. For more than 50 years it was thought that the active constituent was the phenylpropanolamine cathine or (+) norpseudoephedrine. However, in the late 1970s a more potent compound was isolated from fresh leaves and shown to be what is now termed cathinone. Cathinone which is simply �-oxoamphetamine or an oxidized product of norephedrine, is at least as potent as amphetamine as central stimulant.


9 of 41

NH2

CH3

O

Cathinone

As potent as amphetamine

NH2

CH3

OH

Cathine (Norephedrine)

The central stimulants phenmetrazine or 3-methyl-2-phenylmorpholine (obtained by ring formation in cathinone structure) and aminorex possess a benzylic oxygen atom in the form of an ether incorporated in a ring structure. A related stimulant is pemoline which is an alerting agent, useful in attention deficit disorders.

NH2

CH3

O

NH

O

CH3

CathinonePhenmetrazine

Ring Closure

N

O

NH2

NH

O

NH2

O

Aminorex Pemoline

N

O

NH2

OH

Certain stimulant agents which are structurally related to cathinone, such as diethylpropoin, also possesses a benzylic keto group. Diethylpropoin hydrochloride 1-Phenyl-2-diethylaminopropan-1-one hydrchloride


10 of 41

N

CH3

O

Diethylpropoin

The drug has fewer sympathomimetics, cardiovascular and CNS stimulatory effects compared to amphetamine. It is used as anorexient.


11 of 41

Antidepressants The antidepressant drugs are widely used for treatment of mood disorders such as depression, bipolar disorders and also used for the treatment of neuropathic pain, smoking cessation and obsessive compulsive disorders. The following diagram shows the consequencies of the deficiency of the neurotransmitters; serotonin, norepinephrine and dopamine that usually leads to depression .

Serotonin Norepinephrine

Dopamine

Cognitive slowingHypersomniaanhedonia

AnxietyPanicPhobiaObsessive compulsive

Decreased concentrationDecreased working memoryDecreased information processingFatigue

Depressedmood

Food cravingBulimia

Decreased attentionPsychomotor retardation

Syndromes resulting from Deficiency of neurotransmitters and their

interactions

Anhedonia=a psychological condition characterized by inability to experience pleasure in acts which normally produce it. Bulimia= an abnormal and constant craving for food


12 of 41

Development in the medicinal chemistry of antidepressant drugs rendered the recently developed SSRIs in the first line therapy in the treatment of depression. The old generaion antidepressants such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are becoming now less favourable due to their pharmacokinetic profiles and side effects. Thus, with the growing number of drugs used as antidepressants it is very important for clinician and pharmacist to be knowledgeable about the drugs SAR, adverse effects, drug interactions, and pharmacokinetic properties to properly select the optimal drug regimen for the patient. Classes of Antidepressants

• Non-selective (Norepinephrine-Serotonin) reuptake inhibitors • Selective noradrenaline reuptake inhibitors • Selective serotonin reuptake inhibitors • Dopamine and noradrenaline reuptake inhibitors • Serotonin receptor modulators • 5-HT2 and 5-HT3 blockers (antagonists) • MAO inhibitors

��

��

Reuptake is the first step in the process of deactivating these neurotransmitters in the brain. After the neurotransmitters are released from neurons, they are removed from the extracellular space by transporters (also known as reuptake sites) located on the cell membrane. By inhibiting reuptake, the drugs allow serotonin and nor epinephrine to remain active in the synapse longer, thereby correcting a presumed deficit in the activity of these neurotransmitters. They work by correcting imbalance in the brain.


13 of 41

- Tricyclic (TCA) antidepressants are the old generation of this type of drugs. They are

extremely lipophilic, and accordingly, they are very highly tissue-bound outside CNS. - They have anticholinergic and noradrenergic effect, both central and peripheral, that they are

often unpleasant and sometimes dangerous. In overdose, the combination of anticholinergic and antiadrenergic effects, as well as a quinidine-like cardiac depressant effect, can be lethal.

- Their side effects are dry mouth, constipation, urinary retention, sweating. CV effects as hypotension, tachycardia and arrythmias.

Structure-Activity Relation of TCA - The structure of TCA comprised a large bulky group encompassing two aromatic rings,

preferably held in a skewed arrangement by a third central ring. This tricyclic bulky structure lacks coplanirity.

- To the central ring a three or sometimes two-atom chain attached to an aliphatic amino group that is monomethyl- or dimethyl-substituted. These features could be visualized by consulting the structures of imipramine and desimipramine as examples.

- The overall arrangement has features within it approximating a fully extended trans conformation of the �-aryl amines (phenethylamines). The extra bulky group in TCA blocks the uptake process.

- Tertiary amines as imipramine and amitriptyline are more selective inhibitors of 5-HT than catecholamine (NE) compared with secondary amines as desipramine, while in monomethyl metabolites proportion of NA reuptake is higher.

- The treatment begun with dimethylamino derivative and after time there significant

accumulation of mono methyl derivative due to N-demethylation. - Many of the antidepressant drugs are close structural relatives of postsynaptic DA blockers

(antipsychotics) and of NE blockers (sedatives). In fact, many antidepressants retain appreciable antipsychotic and sedative properties.

N

N

H3C

H3C

N

N

H

H3C

Imipramine Desipramine


14 of 41

N

N

H3C

H3C

Imipramine

N

N

H3C

H3C

Clomipramine

Cl

N

H3C

H3C

Amitryptyline

O

N

H3C

H3C

Doxepine

NOREPINEPHRINE and SEROTONIN reuptake inhibitors (NSRIs)Tricyclic members (TCA)

Non-tricyclic members

N

CH3

CH3

H3CO

HO

( )-Venlafaxine

NH2

O

N

( )-cis-Milnacipran

O

N

H CH3

S

S-(+)-Duloxetine

N

N

H3C

H3C

Trimipramine

CH3


15 of 41

Members of TCA

Imipramine Hydrochloride (Tofranil) 5-[3-(Dimethylamino )propyl]-10,11-dihydro-5H-dibenz[b,f]azepine hydrochloride Imipramine may be considered as the parent compound of TCA. It is also close relative to the antipsychotic phenothiazines (isostoric replacement 10-11 bridge with sulfur). Metabolic deactivation proceeds mainly by oxidative hydroxylation in the 2-position followed by conjugation. Metabolic N-demethylation gives nor- (or des-) imipramine. Also N-oxidation is involved.

Clomipramine (Anafranil) 3-Chloro-l0,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine.

Clomipramine has structure similarity with the antipsychotics (e.g. chlorpromazine). It is a strongly sedative and very strong 5-HT up take blocker. It is 50 times more active than imipramine. Its N-demethyl metabolite is reported to be both a 5-HT and NE uptake blocker.

Amitriptyline Hydrochloride (Elavil]

N

N

H3C

H3C

Imipramine

1

2

4

5

N

N

H3C

H3C

Clomipramine

Cl


16 of 41

3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-l-propanamine hydrochloride.

Amitriptyline is one of the most anticholinergic and sedative of the TCA. Since it lacks ring electron-enriching nitrogen atom of imipramine, metabolic inactivation mainly proceeds via benzylic oxidation at position 10- and not 2-position . Metabolic N-demethylation occurs to give nortriptyline which has a less anticholinergic, less sedative and more stimulant action than amitriphyline.

Doxepine Hydrochloride (Sinequan)

3-Dibenz[b,e]-oxepin-11(6H)ylidine-N,N-dimethyl-1-propanamine HCl. N,N-Dimethyl-3-(dibenz[b,e]oxepin-11 (6H)-ylidene)propylamine HCI.

N

H3C

H3C

Amitryptyline

10 11

O

N

H3C

H3C

Doxepine


17 of 41

The oxygen placed is isostere of the -CH2- and this affects oxidative metabolism as well as post- and presynaptic binding affinities. The drug is a NE and 5-HT uptake blocker with significant anticholinergic and sedative properties.The oxygen introduces asymmetry into the tricyclic ring system, resulting in the formation of two geometric isomers: E (trans) and Z (cis). Doxepin is administered as the natural 85:15 mixture of E and Z isomers.

Non-Tricyclic SNRIs Antidepressants

Venlafaxine Venlafaxine is a methoxyphenylethylamine antidepressant that resembles an open TCA with one aromatic ring replaced by a cyclohexanol ring and a dimethyaminomethyl rather than a dimethylaminopropyl chain. Venlafaxine and its active metabolite ODV have dual mechanisms of action, with preferential 5-HT reuptake inhibitory activity and weak inhibition of NE and dopamine reuptake.

N

CH3

CH3

H3CO

HO

( )-Venlafaxine Its major metabolite, 0-desmethylvenlafaxine, shares a similar profile. Neither venlafaxine nor its major metabolite have significant affinity for muscarinic, histaminergic, benzodiazepine, mu opioid, or adrenergic alpha-1 receptors. It is administered as a racemic mixture. Both enantiomers inhibit 5-HT and NE uptake, but the (S)(+)-isomer is more selective for 5-HT uptake.


18 of 41

Venlafaxine possesses an efficacy equivalent to that of the TCAs and a benign side effect profile similar to the SSRl Metabolism of Venlafaxine

N

CH3

CH3

H3CO

HO

( )-Venlafaxine

N

CH3

CH3

HO

HOCYP2D6

ODVEquipotent

Conjugation

CYP3A4

N

H

CH3

H3CO

HO

(Major)

(Minor)Less active metabolite

Duloxetine Duloxetine is an analogue of fluoxetine, in which the phenyl and phenoxy groups of fluoxetine have been replaced, respectively with benzene isostere, thiophene and naphthyloxy group.

O

NH CH3

S

S-(+)-Duloxetine

CF3

O

NH3C

Fluoxetine(Prozac)

H


19 of 41

Metabolism of duloxetine: N-demethylated metabolite is active (CYP2D6). 4-,5- 6- hydroxy metabolites are also formed via hydroxylation of the naphthyl ring, which are subcequently conjugated and excreted in urine as glucuronide, sulfate and O-methylated conjugation products.

Milnacipran


20 of 41

is the cis-aminomethyl derivative of phenylcyclopropanecarboxamide that acts by inhibiting both NE and 5-HT reuptake. It has proven to be save drug. Approxximately 50% of the dose is excerted in urine as unmetabolized drug, 14% is excreted as its N-glucuronide conjugate and the remaining eliminated drug is in the form of conjugated Phase I inactive metabolites. As the unmetabolized drug is the only active form, no dose adjustment is needed in patients presenting liver impairment. It appears to have very favourable benefit:risk ratio, although with a slower onset of action than the TCAs.

Selective noradrenaline reuptake inhibitors (SNRIs)

Despite the current popularity of the SSRIs for the treatment of depression, the norepineprine neurons should not be overlooked, because they also influence the depressed mood. Thus SNRIs may be used alone or as adjunct therapy for treatment of depression.

Tricyclic SNRIs


21 of 41

NH3C

HMaprot iline

N

H3C

H

Nortriptyline

N

N

H3C

H

Desipramine

Selective NOREPINEPHRINE reuptake inhibitors (SNRIs)

N

O

N

N

H

Cl

Amoxapine

(N-desmethyloxapine)(Oxapine is antipsychotic drug)

Phenoxyphenyl-propylamines

O

O

O NH H

O

OH3C

HN

CH3

HN

CH3

O

H3C

S,S-Reboxetine ( )-NisoxetineR-(-)-Atomoxetine

(Non TCA)

N

N

H3C

H

Protriptyline

Desipramine Hydrochloride (Norpramin) 10,11-Dihydro-N-methyl-5H-dibenz[b,f]azepine-5-propanamine monohydrochloride.

N

N

H

H3C

Desipramine


22 of 41

Desipramine is less cholinergic and less sedative, more stimulatory and higher NE than 5-HT uptake-blocking capability. Metabolic deactivation proceeds mainly by oxidative hydroxylation in the 2-position followed by conjugation. Nortriptyline hydrochloride (Aventyl) 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine hydrochloride.

Nortriptyline

Maprotiline Hydrochloride (Iudiomil) N-Methyl-9,10-ethanoanthracene-9(10H)- propanamine hydrochloride.

Maprotiline (Ludiomil)

Maprotiline is a tetracyclic compound, however the compound, conforms to the overall TCA pharmacophore. It is a dibenzobicyclooctadiene that can be viewed as a TCA with an ethylene-bridged central ring. The compound has weak anticholinergic properties and has stimulant property. It is a SNERI. Nontricyclic Secondary Amine Antidepressants Reboxetine It is a nontricyclic SNRI. It is marketed as the racemic mixture although the S,S-(+)-enantiomer has at least two fold inhibition potancy of R,R-enantiomer. Nisoxetine

NH3C

H

N

H3C

H


23 of 41

Nisoxetine is classified as phenoxyphenylpropylamines. The ortho OCH3 gives similarity to norepinephrine receptors rather than serotonin derivatives. R-(-)- Atomoxetine

The R-enantiomer is 10 times more potent than the S-isomer. It is metabolized according to the following scheme.

Selective


24 of 41

Selective Serotonin Reuptake Inhibitors (SSRIs) 5-HT has major role in depressive illness, and serotonergic pathways are closely related to mood disorders, especially depression. Thus, drugs affecting 5-HT levels in the brain may lead to effecive therapy of depression. SSRIs are used for treatment of depression, obsessive-compulsive disorder, and panic disorder and other conditions. Compared to TCAs, SSRIs have reduced adverse-effect profile and better tolerated. SSRIs are expensive drugs, and patient compliance is important during therapy.


25 of 41

F3C O

HN

S-Fluoxetine(Prozac)

F

O

N

NC

Escitalopram

Selective Serotonin reuptake inhibitors (SSRIs)

Phenoxyphenylalkylamines

F3C O

H2N

S-Norf luoxetine

(S)(S)

F

HN

OO

O

(-) 3S,4R-Paroxetine

(S)(R)

F3C

N

O

NH2

O CH3

Fluvoxamine

Cl

Cl

NHCH3

Sertraline


26 of 41

Fluoxetine

Fluoxetine is potent and selective inhibitor of 5-HT reuptake, but not NE or Dopamine. Both enentiomers of fluoxetine display similar affinities to human SERT. However, the S-enentiomer is approx. 100 times more selective for SERT inhibition than thr R-enentiomer. The S-(-)-norfluoxetine metabolite is 7 times more potent as an inhibitor of the 5-HT transporter than the R-(+)-enantiomer. Paroxetine

Paroxetine is a constrained analogue of fluoxetine in which the linear phenylpropylamine has been folded into piperidine ring. It contains two chiral centers and only the (-)-3S,4R-Paroxetine is marketed as paroxetine. It is potent and selective inhibitor of SERT. It is metabolized by CYP2D6 to the catechol metabolite, which is then O-methylated or O-glucuronidated.


27 of 41

F

HN

OO

O

F

HN

OHO

HO

CYP2D6

O- methylationOR

O-glucuronidationMetabolism of Paroxetine

Escitalopram

Citalopram is considered as constrained form of paroxetine. Therapeutic activity of citalopram resides in the S-(+)-isomer (Escitalopram). The S-enantiomer has high affinity and selectivity to human SERT. It is reported that the R-isomer counteracts the action of the S-enantiomer.


28 of 41

F

O

N

NC

F

O

HN

NC

F

O

H2N

NC

CYP2C19CYP2D6CYP3A4

CYP2D6

Escitalopam

Metabolism of Escitalopram

Negligable inhibitor of SERT

Negligable inhibitor of SERT

Sertraline


29 of 41

Sertraline appears as structurally different drug, yet, the diphenylpropylamine nucleus is constrained into bicyclic rigid ring system. It contains two chiral centers and only the S,S-(+)-diastereoisomer is markted. Srtraline is primarly metabolized by CYP3A4 to N-demethylsertraline (5-10 times less potent 5-HT reuptake inhibitor tha sertraline). Oxidative deamination and ring hydroxylation followed by glucuronidation are also metabolic pathways.

Cl

Cl

NHCH3 Cl

Cl

NH2CYP3A4

Cl

Cl

NH2

Cl

Cl

O

OH

O-glucuronidation

Metabolism of sertraline

Fluovoxamine


30 of 41

Fluvoxamine is structurally unique among SSRIs. The E-isomer is the active one. Solution of E-isomer, if exposed to UV-B light, photoisomerization to the pharmacologically inactive Z-isomer occurs.

Metabolism of Fluvoxamine

F3C

N

O

NH2

O CH3

F3C

N

O

NH2

OH

F3C

N

O

NH2

OH

O

CYP2D6

Oxidative deamination

F3C

N

O

OH

O

H

[O]

Serotonin Receptor Modulators Serotonin Antagonist/Reuptake inhibitors (SARIs) This is a class of antidepressant drugs that modulate the concentration of serotonin in the brain. As the serotonergic system modulates a large number of physiological events, such as temperature regulation, sleep, learning and memory, behavior, sexual function, hormonal secretions, and immune activity, and is implicated in stress, anxiety, aggressiveness, and depression disorders. Trazodone Trazadone, a second-generation antidepressant, possesses complex mechanism of action Trazodone is a phenylpiperazine-triazolopyridine antidepressant that is structurally unrelated to other antidepressants.


31 of 41

Trazodone acts as an antagonist at 5-HT2A receptors and is a weak inhibitor of 5-HT reuptake at the presynaptic neuronal membrane, thus potentiating the synaptic effects of 5-HT. Chronic SARIs modulate 5-HT receptor expression and, in turn 5-HT function. Chronic antidepressant treatment with SAPIs modulate 5-HT receptor expression and, inturn, 5-HT function.

Interestingly, it is metabolized to m-chlorophenylpiperazine, a known agonist at 5-HT receptors and an inhibitor of 5-HT reuptake.

N

N

NN

N

O

Cl Trazodone

OH

N N

N

O

O

N NH

Cl

+

CYP3A4

CYP3A4

N

N

NN

N

O

Cl

HO

2e

N

N

Cl

O

iminoquinone

N

N

Cl

HO

SG

GSH

Glutathione adduct

N

N

NN

N

O

Cl

HO

O

m-chlorophenylpiperazine

N

N

NN

N

O

Cl

HO

OH

OH

N

N

NN

N

O

Cl

HO

OH

Nu

Nu

Hepatotoxicity

Metabolism of trazodone


32 of 41

Dopamine and norepinephrine reuptake inhibitors (DNRIs) Bupropion It is structurally related to phenylisopropylamine CNS stmulant, methamphetamine, cathinone and diethylpropion.

�

��

�

��

��

��

�

��

��

��

��

�

��

��

��

��

��

��

��

��

��

Bupropion reduces the discomfort and craving associated with smoking cessation. Mechanism is unclear.


33 of 41

alpha 2-adrenergic autoreceptor blocker Mianserin

N

N

CH3Mianserin

Mianserin is a tetracyclic antidepressant whose postulated mechanism of action involves release of noradrenaline mediated via cortical alpha 2-adrenergic autoreceptor blockade. This property resides stereoselectively in the S(+)-enantiomer of mianserin, which is also more potent in behavioural tests indicative of antidepressant activity, and in the reversal of clonidine-induced effects. Noradrenergic Specific Serotonergic Antidepressants(NSSA) Mirtazapine Mirtazepine is a piperazinodibenzoazepine antidepressant that is an isostere of the antidepressant mainsrin.

� �

�

��

The isosteric replacement of an aromatic CH in mainserin with N to give pyridine ring in mirtazepine has profound effects on the physicochemical properties, pharmacokinetics, mode of action, and antidepressant activity of both drugs. The pyridine ring increases the polarity of the molecule and deceases the LogP and basicity. While mainserin is potent


34 of 41

inhibitor of NET (norepinephrine reuptake transporter), mirtazepine has negligable effect on the inhibition of NET. Mirtazapine mode of action proceeds via enhancing central noradrenergic and serotonergic activities; possibly through blocking central presynaptic �2-adrenergic receptors which results in inhibition of the negative feedback loop, that increases the release of NE into synapse. It is also potent antagonist at 5-HT2 and 5-HT3 receptors. Mirtazapine has some anticholinergic properties, and H1 antihistaminic activity that results in producing sedative effects. It also produce orthostatic hypotension because of moderate �1-adrenergic antagonist activity.

Monoamine oxidase inhibitors (MAOIs)

Once the brain's three neurotransmitters, monoamines, (serotonin, norepinephrine, and dopamine), have played their part in sending messages in the brain, they get burned up by


35 of 41

monoamine oxidase, a liver and brain enzyme. MAO catalyzes the oxidative deamination of various amines, including epinephrine, NE, dopamine, and 5-HT. The mechanism of antidepressant action of the MAOIs suggests that an increase in free 5-HT and NE and/or alterations in other amine concentrations within the CNS is mainly responsible for their antidepressant effect. MAO enzymes may be subdivided into two isoenzymes. MAO-A that preferentially metabolizes 5-HT and NE and reversibly inhibited by moclobemide. MAO-B is preferentially located in human platelet that is irreversibly inhibited by pargyline.

MAO exists in at least two isozymic forms termed MAO A and MAO B. The main difference in these two isozymes is their selectivity for the oxidation of the various biogenic amines. Because the antidepressant effect is related to increased concentration of brain serotonin and norepinephrine, both of which are MAO A substrate, compounds that selectively inhibit MAO A possess antidepressant activity; selective inhibitors of MAO B show potent antiparkinsonian properties As it inhibits dopamine catabolism. To have antidepressant drug without the cheese effect (Severe hypertensive responses (cheese reaction), sometimes fatal, have followed ingestion of foods high in pressor amines; tyramine, as hot dogs, beans and sour cream), however, it is necessary to inhibit brain MAO A selectively without inhibition of peripheral MAO A, particularly MAO A in the GIT and sympathetic nerve terminals. Inhibition of brain MAO A increases the brain serotonin and norepinephrine concentration, which leads to the antidepressant effect; the peripheral MAO A must remain active to degrade the peripheral tyramine and norepinephrine that cause the undesirable cardioselsctive effects.

NH2

HO

TYRAMINE


36 of 41

These drugs were prescribed with strict dietary regulations. MAO inhibitors are not the drug of choices, except in those types of depression that do not respond to tricyclic antidepressants. Parkinson’s disease is characterized by a reduction in the brain dopamine concentration. Dopamine is metabolized by MAO B in man; selective inactivation of MAO B has been shown to be an effective approach to increase the dopamine concentration and, thereby, treat this disease. Actually a MAO B-selective inactivator is used in combination with the antiparkinsonian drug L-dopa. Selective inhibition of MAO B does not interfere with the MAO A-catalyzed degradation of tyramine and norepinephrine; therefore, no cardiovascular side effects (cheese effect) are observed. Selegiline was approved by FDA for the treatment of Parkinson’s disease

Members of MAOIs First generation MAOIs; Irreversible, Nonselective Tranylcypromine sulfate (parante) (±)- Trans-2-phenylcyclopropylamine Sulfate

Tranylcypromine Tranylcypromine has some amphetamine-like properties. Tranylcypromine is a mechanism-based inactivator and it is metabolized by MAO. One electron of the nitrogen pair lost to flavin, and this, in turn, produces a homolytic fission of a carbon-carbon bond of cyclopropane, one electron from the fission pairing with the remaining lone nitrogen electron to generate an imine (protonated), the other residing on a methylene carbon. Thus, a free radical is formed that reacts covalently with either the enzyme or with reduced flavin resulting in MAO inactivation. It is metabolized by MAO according to the following mechanism:-

NH2


37 of 41

Phenelzine

OHN

NH2 NH NH2

Isoniazid Phenelzine

During clinical trials with the antiTB drug isoniazid, mood elevation was noted in depressed patients with tuberculosis. Structure development of isoniazid to produce antidepressant drugs led to the synthesis of phenelzine. Phenelzine produces prolonged, non-selective, irreversable inhibition of MAO.

Second Generation MAOIs : Irreversible, Preferential (S)-Deprenyl, Seligiline N-Methyl-N-2-propynyl-�-methylphenethylamine

NH2Flavin

CH2

NH2

FlavinCH2

NH2

Flavin

+ +free radicale

CH3

NH3C CH

H


38 of 41

Deprenyl has the advantage of sparing liver MAO-A and thereby, avoid the "Chesse effect'' or hypertensive response to tyramine and other dietary pressor amines. An effect of deprenyl involves preferentially MAO-B inhibitor which predominates in dopamine-containing regions of CNS. It is used in the treatment of parkinson's disease.

Third Generation MAOI: Reversible, Preferential Newer MAOIs are specific for MAO-A. MAOA is involved in controlling NA and 5-HT levels in depression pathways. Still have to be careful with tyramine consumption in diet. Meclobemide is an example of this class.

Moclobemide 4- Fluoro-N-[2-(N-morpholino)ethyl]benzamide Moclobemide is reversible and preferential MAO-A inhibitor

Mood stabilizers Lithium is a monovalent cation that competes with sodium, potassium, calcium, and magnisium ions at intracellualr binding sited; at sugar phosphatases; at protien surfaces; at carrier binding sites; and at transport sites. These effects result in reduction of signal transduction through the phosphatidylinositol signaling pathway.

NH

Meclobemide

O

F

N

O


39 of 41

Lithium mode of action

PIP

PIP2

G IP3

IP2

IP1

InositolPI

X Li+

PLC

DAG

Ca 2+

PLC= Phospholipase (a membrane bound enzyme), IP= inostitol monophosphate; DAG= diacylglyceride

4- Hallucinogens “Hallucinogen” is derived from the Latin term “hallucinari”, which means to wander in the mind. They are defined as: - Psychedelic: alters consciousness. - Psychotomimetic: mimics psychosis. - Psychotogenic: produces psychosis. Indicators of Hallucinogen Abuse: Hallucinations, dazed appearance, disoriented, uncoordinated, body tremors, paranoia, difficulty in speech and nausea. Hallucinogens - Cannabinoids - Phencyclidine (PCP)- Street Names: PCP, Angel Dust, Supergrass, Boat, Tic Tac, Zoom, Shermansrelated Agents


40 of 41

Phencyclidine

- Indolealkylamines - Phenylalkylamines

Cannabinoids

� The marijuana or cannabis plant represents of the most widely used psychoactive substances in the world

� One of the major active constituents of the plant is �9-tetrahydrocannabinol (�9-THC; often referred simply as THC) - THC is rapidly and efficiently absorbed by inhalation; it is absorbed into body tissue and slowly released back into circulation - A major metabolite of THC is 11-hydroxy-�9-THC - There is evidence that THC generally lead to tolerance develops to THC, and that is THC does not generally lead to physical dependence �9-THC 11-Hydroxy-�9-THC Agent possessing an indolethylamine and a phenylethylamine moiety Lysergic Acid Diethylamide (LSD)

� Is the most potent drug by weight, and is the most thoroughly researched.

O

H3C

H3C

CH3

OH1

2

3

4

6

7

8

9

10

5 O

H3C

H3C

CH2OH

OH1

2

3

4

6

7

8

9

10

5


41 of 41

� Is often impregnated in sugar pills, blotter paper, or small gelatin squares for ingestion.

� Can produce profound effects on thinking, self-awareness, and emotions. � Physical dependence is unlikely, however psychological dependence is common

in long-term users.

LSD

NH

NH

O

N

CH3

cns stimulants & antidepressants central nervous system

Documents