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DOPAMINE RECEPTORAnionic site on receptor tointeract with the protonatednitrogen of dopamineA flat, hydrophobic areathat interacts with thephenyl ring and hydrogenbonding at specific areasaround the phenyl ring toaccommodate the ringhydroxylsA two carbon distancebetween the anionic site andthe ring site
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
Electron withdrawing group at C2 S N e- α βIncreases potency γ R2 N R1
The most potent position for the electron withdrawinggroup is C2 which may help bending the side chain Nthrough H bond to form dopamine-like conformationThe rank order of potency is position 2>3>4>1Substitution at C1 has deleterious effect on antipsychoticactivity (which may interfere the bending as in 1) as does(to a lesser extent) substitution at C4 which may interfere Sbinding to receptorStronger electron withdrawers are more potentMore than one substitution on the ring system decreasespotencyOxidizing the ring-sulfur to sulfoxide or sulfone reducespotency
CH3 CH2 CH3 H3C CH3H CH3 CH2 CH2 CH3 CH3 CH3 CH3 CF3 N CF3O H O CH3 O C O C O C O S O Cl S O S S O S O O S O CF3 Least potent Most Potent
ALKYL SIDE CHAIN CH3Increasing or decreasing thelength from 3 carbons N N CH3decreases the potency. The Sfurther from 3 the lesspotent. Two carbon side Fenethazinechains increase H1antagonism (Fenethazine)Substitutions on the αcarbon decrease potency CH3 N NA methyl substituent on theβ carbon can increase or S CH3 CH3decrease dopamineantagonism (Trimeprazine) Trimeprazine
A methyl substituent on theβ carbon increases H1antagonism. Substituents CH3that are larger than methyl N Ndecrease antihistaminic Sactivity unless they are partof a heterocycle Methdilazine(Methdilazine)Substituents on the γ carbondecrease dopamineantagonism but increase N Nanticholinergic activity. S CH3These would be expected toproduce less extrapyramidal CH3side effects. All the Spiperidines fit this category Thioridazine
Bridging of position 3 of theside chain to position 1 thephenothiazine significantlyreduces neuroleptic activity
SUBSTITUENTS ON THE γ NITROGEN There are three classes of phenothiazines based on the nature of this substituent 1. N,N-Dimethyl (aliphatic) 2. Piperazine 3. Piperidine
Thioridazine S N SPiperidine ring α CH3Low EPS risk βCentral antimuscarinicQTc prolongation CH3 N
Fluphenazine S N CF3Piperazine ring α β N N OH
BASIC AMINO GROUPMaximum neuroleptic potency is observed inaminoalkylated phenothiazines having a tertiaryamino group.In general, alkylation of the basic amino group withgroups larger than methyl decreases theneuroleptic potency.Quaternization of the terminal nitrogen result inloss of activity due to inability of these polarcompounds to cross the BBB.
POTENCY COMPARISONPotency at the D2 receptors:Given equal C2 substituents, ranked from mostpotent to least potent - Piperazine > Aliphatic >PiperidineOf drugs on the market, however, the rank is -Piperazine > Piperidine > AliphaticAnticholinergic potency: Piperidine > Aliphatic >Piperazine
α Receptor antagonism: Aliphatic > Piperidine >Piperazine (This may be due to the fact that inorder to get a good antipsychotic effect (D2antagonism) large doses must be given and so theα receptor antagonism, although weak, is seenmore)Extrapyramidal side effects: Piperazine > Aliphatic> Piperidine (Low anticholinergic potency in thepresence of strong D2 block)Sedation: Piperidine > Aliphatic > Piperazine
History/Evolution of Butyrophenone O OC2 H5 CH 3 N Meperidine O O OC2 H5 N Propophenone 200 x Meperidine as an Analgesic O OC2 H5 N Butyrophenone Analgesia s imilar to Meperidine O Other activity similar to Chlorpromazine F OH N Haloperidol (Haldol) O Prototype butyrophenone antipsychotic 10x Chlorpromazine Cl
BUTYROPHENONE R1 O Y R2 N X – electron donating group has highest potencyX Changing the length of the propyl chain decreases potency Replacing the keto oxygen with S, carbon, OH decreases potency Y – Replaced with N – Piperazine structure
O F N NH N O Drope ridol (Inapsine) OtherButyrophenone F OH Nantipsychotics O CF3 Triflupe ridol O F H N N NH F Pimozid e (Orap) "diphenylbu tylpiperidine" similar to haloperidol, longer duration. Used for Tou rettes Syndrome.
Clozapine 7 member central ring Moderate potency at DA α1 and α2 adrenergic, 5-HT1A, 5-HT2A, 5-HT2C, M, H1
Quetiapine Lack a substituent on the aromatic ring
Other atypical Resperidone is benzisoxazole andantipsychotics ziprasidone is the benzisothiazole containing antipsychotic agents H3C N Risperidone is 5-HT2A/D2F N N antagonist with relatively high O affinity at histamine H1 and O N Risperidone adrenergic a1 and a2 receptors. It Cl H N has less extrapyramidal side HCl O effects N N Ziprasidone is also 5-HT2A/C/D2 S N Ziprasidone 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
Other atypical antipsychotics NNH N S N CH3 H3 C Olanzapine Loxapine
Aripiprazole H O N O N N Cl Aripiprazole ClIt is an arylpiperazine quinoline derivative with complexpharmacology. Dopamine D2 and serotonin 5-HT1A & 5-HT2A/C receptor inhibitions are believed to be involved inits antischizophrenic therapy. It has high affinity partialagonist effect to some D2 receptors depending on celltype, which explain its low extrapyramidal side effects.
CURRENT CONCEPTSPresently, antipsychotic agents include many differentchemical structures with a range of activities at differentneurotransmitter receptors (e.g., 5-HT2A antagonism, 5-HT1A partial agonism).As a result, structure-function relationships that were reliedupon in the past have become less important.Instead, receptor-function relationships and functionalassays are more clinically relevant.Aripiprazole represents a good example of how anexamination of the structure provides little insight into itsmechanism, which is based on dopamine partial agonism.