Antipsychotics Med chem lecture


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Lecture Notes for B. Pharm, Medicinal Chemistry of Purbanchal University Nepal regarding Antiphycotics

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  • If there is more dopamine action in the mesocortical pathway in Schizophrenia, then the patients should always be in euphoric state. But instead patient lacks motivation and want for pleasure. Why?Also can we selectively block D receptors in Mesocortical and Mesolimbic pathway?
  • Note: Put example here
  • Ref:Paul A. J. Janssen, Willem FRef:Paul A. J. Janssen, Willem F. M. Van BeverStructure-Activity Relationships of the Butyrophenones and DiphenylbutylpiperidinesHandbook of Psychopharmacology,1978, pp 1-35. M. Van Bever
  • Effect of ROCORvs RCOOR? 1)1st is moderate EDG, 2nd is moderate EWG. But both are two CH2 units away, too far for induction to be a major factor2) Why so much high Duration of action? Esterification is a prodrug approach and should be degraded right away.
  • Eli Lilly has faced many lawsuits by from people who claimed they developed diabetes or other diseases after taking Zyprexa. In 2006, Lilly paid $700 million to settle 8,000 of these lawsuits.[78] In 2007, Eli Lilly agreed to pay up to $500 million to settle 18,000 more lawsuits.[citation needed]In 2009 Eli Lilly pled guilty to a criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion.[79] Although Lilly had evidence that it is not effective for dementia, Zyprexa was marketed for elderly Alzheimer's patients.[80] The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis
  • Antipsychotics Med chem lecture

    1. 1. Antipsychotics There is no cure for Schizophrenia just symptomatic control is done
    2. 2. Schizophrenia • A mental disorder where person can’t grasp reality and shows behavioral and cognitive dysfunction • Positive symptoms: abnormality of normal function leading to presence of inappropriate behaviors – Delusions (false belief)and hallucination (false perception), speech disturbances • Negative symptoms: loss of normal function leading to absence of appropriate behaviors – lack of motivation, social withdrawal, lack of interest in fun activity, doesn’t respond to questions SCHIZOPHRENIA IS FOR LIFE
    3. 3. Causes We don’t know the exact cause but it is believed that excess of dopamine activity is the reason for the disease The evidence for this is- • 1st Drugs for psychosis was Chlorpromazine and it is a D2 antagonists • Antiphycotic drugs produce Parkinson-like symptoms • Drugs that promote dopamine activity, L-Dopa and amphetamine, produce or increase Schizophrenia • There is increase in number of brain dopamine receptor .
    4. 4. Counter evidence of the dopamine hypothesis • Older drugs are not effective in all patients • Newer atypical drugs low affinity for dopamine receptors • Drugs that block NMDA produce more Schizophrenia than even drugs that promote dopamine This suggests other NT than dopamine is also involved
    5. 5. Major Dopamine pathways Pathway Significance Associated disease The Nigro-straital pathway Movement Low dopamine causes EPS (Extra Pyramidal symptoms) The Mesocortical pathway Motivation, pleasure, socialization High Dopamine causes negative symptoms of schizophrenia The Mesolimbic pathway Speech, grasp of reality High dopamine causes positive symptoms of schizophrenia The Tubero infundibular pathway Prolactin Hormone release Prolactin Hormone deficiency Ideally we would want dopamine blockade only in Mesocortical and Mesolimbic pathway but that has not been realized till now
    6. 6. Dopamine and EPS • We studied in Parkinson that Dopamine is a Neurotransmitter (NT) involved in movement (in balance with acetylcholine) • When dopamine levels decreases, due to action of antipsychotic drugs in all Dopamine pathways, movement related disorders called Extra Pyramidal symptoms (EPS) arise which includes – akinesia (inability to initiate movement) and – akathisia (inability to remain motionless) and – acute dystonia (twisting of muscles)
    7. 7. Other Neurotransmitters also have their own pathways and unique function associated with it
    8. 8. • DOPAMINE RECEPTORS Receptor 2o Messenger System D1 cAMP D5 cAMP D2* cAMP, D3 cAMP, D4 cAMP *Most antiphycotic drugs antagonize or inverse agonize block D2 but newer atypical drugs have other mechanism too based on acetylcholine, histamine, serotonin, adrenaline
    9. 9. Ideally receptor are silent or non-functional without being bound by their natural agonist. But some receptor are active even when they are not bound by any agonist. In this case inverse agonists work to produce opposite response. Inverse agonism is a property seen in only those receptors (not enzymes) that are active even without any binding to their agonist/ligand/substrate. Ref: Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 6, page 181-184 2004 Understanding Inverse Agonism
    10. 10. • Inverse Agonist produce negative response
    11. 11. Classification 1st Gen/Typical: High affinity for Dopamine receptor and consequently have Extra Pyramidal symptoms (EPS) • Butyrophenones: Haloperidol*, Droperidol • Phenothiazines – Aliphatic : Chlorpromazine*, Trifluopromazine – Piperidine : Thioridazine, Piperacetazine – Piperizine : Fluphenazine, Perfenazine • Thioxanthines: Flupenthixol, Thiothixene 2nd Gen/Atypical: They primarily affect other NT but for exact reason have a wide Side effect profile including obesity • Olanzapine, Quetiapine, • Aripiprazole, Risperidone
    12. 12. P o t e n c y
    13. 13. Discovery of Butyrophenones
    14. 14. SAR of Butyrophenones 1) Modification of benzoyl group • Anything other than fluorine in the para position lowers activity • A is 4 times more potent than B due to F C O CH2 N 3 F C O CH2 N 3 A B
    15. 15. 2) Replacing the carbonyl group with isoteric group or any other functional group lowers activity X can’t be N or S or C X can’t be OH, NH2, SH
    16. 16. An important exception - Diphenylbutylpiperidines Replacement of the carbonyl of haloperidol with para fluro phenyl group creates a new class of compounds called diphenylbutylpiperidines that has following advantage –Long acting –NO sedative, autonomic, extrapyrimidal side effects –Useful in autism (Autism is a mental disorder in children characterized by impaired social interaction and verbal and non-verbal communication, and by repetitive behavior)
    17. 17. Diphenylbutylpiperidines The keto group has been replaced with para Fluro group
    18. 18. 3) Modification of the -CH2- linker group The linker has to be a propylene. Any alteration to the -CH2- linker region such as shortening, lengthening, branching, or incorporation into a ring system, results in a marked decrease or even complete loss of neuroleptic activity. C O CH2 N n F only n= 3 is active R2 R1 NC O F R1 R2no cyclic form allowed
    19. 19. 4) Modification of the amino group a) A tertiary amino group should be present b) A tertiary amine in some cyclic form (piperidine, tetrahydropyridine or piperazine ring) increases potency c) Further modification of the ring at para position can de done for better potency and reducing toxicity
    20. 20. P o t e n c y Ref:Paul A. J. Janssen, Willem F. M. Van Bever Structure-Activity Relationships of the Butyrophenones and Diphenylbutylpiperidines Handbook of Psychopharmacology,1978, pp 1-35 •R is always amine •Amine is always teritary •It can be para substituted for better potency or lower toxicity
    21. 21. Haloperidol • It is a Butyrophenone derivative used in the treatment of schizophrenia and delirium • It has High incidences of Extra Pyrimidal Side efects(EPS – tremor and motor dysfunction) but Low hypotension and low autonomic side effects and sedative effects lower than Chlorpromazine • Decanoate Esterifation at the OH group forms a long acting derivative • MOA- It is an inverse agonist in Dopamine D2 receptor in the Mesocortical and Mesolimbic pathway Ref: British Journal of Pharmacology (1997) 121,731± 736
    22. 22. Haloperidol synthesis CH2CH2CH2Cl C O Cl F CH2CH2CH2Cl C O F 4-Chlorobutyryl Chloride Fluorobenzene 4-Chloro-4-fluorobutyrophenone -HCl Cl NH HO 4-(p-Chlorophenyl)-4-piperidionol Cl N HO CH2CH2CH2 C O F -HCl Haloperidol
    23. 23. SAR of Phenothiazines
    24. 24. SAR of Phenothiazines 1) Unsubstituted Phenothiazines has no activity but has enough lipophilicity for good brain penetration. Substitution at C2 and N10 is required for activtiy
    25. 25. 2) C2 must have an electrowithdrawing group. The activity for these various group is as X = - SO2NR2 > -CF3 > -CO-CH3 > -Cl
    26. 26. Electron Donating Electron Withdrawing
    27. 27. 3) A terminal amino substituent must be present at N10. It can be piperazine, piperidine or aliphatic and their intensity could be ranked as follows: piperazine group >piperidine group > aliphatic chain
    28. 28. •Esterification of the OH containing piperazine derivatives extensively increases the duration of action
    29. 29. 4) There must be an linear (ie unbranched) alkyl linker between the core ring and the terminal amino ring those length is optimum at three methylene units ie CH2-CH2-CH2 Reduction of these carbon number changes receptor affinity
    30. 30. Chlorpromazine • It is a phenothiazine derivative used in treatment of schizophrenia. It was the first antiphycotic drug • It’s also used as antiemetic and against hippcup • Has high incidence of Extra Pyramidal side effects • It’s metabolite has strong antiadrenergic, weak anticholinergic and slight antihistaminergic and antiserotonergic properties (not parent molecule) • MOA: It antagonizes Dopamine D2 in the the Mesocortical and Mesolimbic pathway
    31. 31. Chlorpromazine synthesis S N Cl H Cl CH2 CH2 CH2 N CH3 CH3 3-Chloropropyl-dimethylamine 2-Chlorophenothiazine Refulx in presence of toulene and sodamide S N Cl CH2 CH2 CH2 N CH3 CH3 Chloropromazine
    32. 32. R1 R2 R1R2 Trans has R groups on opposite side of double bond Cis has R groups on same side of double bond Decide cis and trans in these compounds?
    33. 33. Flupenthixol • It is a Thioxanthine derivative used for treatment of schizophrenia • It can exist in cis and trans form and only cis is active because it mimics the conformation of Dopamine • It’s duration of action is long (2-3 weeks) and hence useful in patients who have a poor compliance with medication MOA- It is nonselective and antagonizes both Dopamine D1 and D2 in the the Mesocortical and Mesolimbic pathway
    34. 34. Olanzapine • It is an atypical drug used for treatment of of schizophrenia and also used in bipolar disorder • Olanzapine is a potent antagonist of the muscarinic M3 receptor and this has been linked to it’s diabetic side effect • It can cause heart failure, sudden death, or pneumonia when used in older adults suffering from dementia • MOA: It has low antagonist activity in Dopamine D2 receptor and primary action is believed to have occurred through inverse agonism at Serotonin 5HT2A and antagonism at adrenergic receptors
    35. 35. Schizophrenia vs Dementia Schizophrenia Dementia Both Positive and Negative symptoms MUST occur multiple cognitive problems occur Schizophrenia is independent disease It is a physiological result of an illness or substance eg Dementia in Parkinson and Alzheimer
    36. 36. Quetiapine • It is a short-acting atypical antipsychotic used for the treatment of schizophrenia and bipolar disorder • It is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with negligible anticholinergic properties. • MOA: It has low antagonist activity in Dopamine D2 receptor and primary action is believed to have occurred through antagonism at both Serotonin 5HT2A and adrenergic receptors
    37. 37. Aromaticity Which one of these tricyclic rings is flat?
    38. 38. Aripiprazole • It is a atypical antipsychotics used in the treatment of schizophrenia, bipolar disorder, irritability associated with autism and as an adjunct in depression • Extra Pyramidal Side effects is low • It agonizes 5HT2C also which control satiety. Thus this drug does not cause weight gain which is seen with other antiphycotic drug • MOA: It is a partial agonist at both Dopamine D2 and Serotonergic 5HT2A receptors
    39. 39. Drug Dopamine (D2) Serotonin (5HT2A) Adrenergic Haloperidol Inverse agonist No action by 1st Gen No action by 1st Gen Chlorpromazine Antagonist No action by 1st Gen No action by 1st Gen Flupenthixol Both D1 & D2 antagonist No action by 1st Gen No actionby 1st Gen Olanzapine Weak Antagonist Inverse agonist Antagonism Quetiapine Weak Antagonist Antagonist Antagonist Aripiprazole Partial agonist Partial agonist - Summary: The MOA of antipsychotic Drugs are not the same
    40. 40. THANK YOU
    41. 41. Revision Special topic Antipsychotic Drugs can make you fat. So fat that it can kill you!!! Neuropsychiatric Disease and Treatment 2008:4(1)
    42. 42. • People suffering from schizophrenia, on average, die about 25 years earlier than individuals from the general population. • Some of this reduced life expectancy is due to Coronary heart disease (CHD) which is turn is due to high cholesterol due to obesity Ref: Focal Point: Youth, Young Adults, & Mental Health. Healthy Body - Healthy Mind, Summer 2012, 26(1)
    43. 43. Antipsychotic drugs increases appetite You become fat Arteriole wall are squeezed by fat deposition Coronary Heart Disease Question is how does antipsychotic drugs make you fat?
    44. 44. • Research led to finding that activation of TGFβ1/SMAD3 signaling pathway led to obesity based side effects • Blockade of SMAD3 was speculated to counter obesity • Mouse who has their SMAD3 knocked out (alteration in their DNA so that no SMAD3 is produced by body naturally) did not become diet induced fat* • Also, the antiphycotic action and obesity action were completely independent from each other. * Ref: Protection from obesity and diabetes by blockade of TGF-β/ Smad3 signaling Cell Metab. 2011 July 6; 14(1): 67–79.
    45. 45. Antiphycotic drugs Activate SMAD3 Activate PPAR Activate Adipogenesis (increase in fat cells) This is how antipsychotic drugs and obesity are connected Ref: Getting ‘Smad’ about obesity and diabetes. Nutrition and Diabetes (2012)2, e29
    46. 46. It means • It is possible to create antiphycotics drugs that DO NOT cause obesity (ie enhance selectivity to avoid SMAD3 receptor blockage) • SMAD3 can be a new independent target to reduce obesity Lesson to learn: Pharmacology is a cool subject • The side effects of antipsychotics drugs was investigated and a good target for completely different diseases was established
    47. 47. 2.5 marks questions 1. How do atypical antipsychotic drugs differ from typical ones? 2. What is the meaning of positive and negative symptoms of Schizophrenia? 3. How antipsychotic drugs cause Parkinson? 4. What is unique about Aripiprazole in context of obesity?