Lecture 10: Development of treatments associated with affective & psychotic disorders.

Question 1

What are atypical antipshychotics?

Answer 1

Drugs that affect seratonergic neurotransmission. Olanzapine, risperidone and clonazapine also amisulrpide, aripiprazole and many more. Olanzapine and clonazapine are often referred to as belonging to the tricyclic antipshcoticcs (three fused rings). They are 5-HT2a receptor antagonists and also bind 5HT2c (and dopamine receptors, hence called atypical)

Question 2

What are the clinical implications of 5-HT2A Receptor and receptor antagonists?

Answer 2

Role in thermoregulation and sleep. Could also be involved in appetite control, learning and cardiovascular function an d muscle contraction. 5-HT2C antagonism could be useful in the treatment of anxiety, sleep and mood disorders

Question 3

What was the first atypical antipsychtocic discovered? What are its properties?

Answer 3

Clonazapine. It is a benzazepine analoge. 5HT2a receptor antagonist, it also binds 5HT2c. Oral bioavaialaility 60-70%. Half life 13 hours. metabolised primarily by CYP1A2

Question 4

What are the properties of olanzapine?

Answer 4

metabolised primarily by CYP1A2. Bioavailability 40-50%. Half life 20-50 hours

Question 5

What is the dopamine hypothesis in schizophrenia?

Answer 5

Arose from early observations of phenothiazines and thier effect on dopamine metabolism. The hypothesis being that schizophrnia results from increased dopaminergic neurotransmission. Approaches which decrease dopaminergic neurotransmission will alleviate psychotic symptoms. Most antipsychotic agents have actibity to limit dopaminergic neurotransmission. It is believed that extrapyramidal side effects are reduced in drugs with less affinity for D2 receptors

Question 6

What antipshychotics are more effective at tretaing negative symptoms of schizophrenia such as anhedonia, avolition, and apathy?

Answer 6

Atypical antipsychotics. Can also be used for autism since the negative symptoms of schizophrenia have similarities to the social impairment characteristic of autism.

Question 7

How do ADHD treatments act?

Answer 7

ADHD treatments act as psychostimulants, acting to block the reuptake of Noradrenaline (NE) and Dopamine (DA) (Methylphenidate) or to increase synaptic concentrations of NE and DA (Dexamfetamine)

Question 8

What are the properties of methylphenidate?

Answer 8

• Cocaine related agent - not structually but in terms of pharmacological profile
• Binds the DA transporter preventing the reuptake of DA
• 2 chirals at centres C2 and C2’
• Potentially 4 isomers
• Ritalin is a mixture of R,R (+)-threo and S,S (-)-threo
• The R,S (+)-erythro and S,R (-)-erythro forms are inactive

Question 9

What are the properties of dexamphetamine?

Answer 9

• Is the S isomer which is several fold more potent than R form in terms of its central stimulation actions
• R form is called levoamphetamine
• Relative potency may not be reflected in the periphery, such as cardiovascular functions

Question 10

What is the structure related activity of dexamphetamine as a central stimulant?

Answer 10

1. Substitues on aryl ring diminish or abolish activity
2. p-hydroxyl substituent has little activity and unlikely to penetrate BBB
3. Methyl ester has about 10% potency
4. 4 methyl group has little to no activity at all
5. Removing methyl at alpha carbon gives phenylethylamine which lacks central stimulant actions - ethyl and n-propyl have no activity
6. Tertiary < Secondary < Primary amines - Exception is N-monomethyl substituent which is 2-3x more potent – this is methamphetamine, one of the most widely abused substances in the world. Activity abolished as N-Substituents get larger

Question 11

What is the seratonin hypothesis of depression?

Answer 11

5-HT is a major factor in depressive illness, and 5-HT pathways are linked with mood disorders such as depression. Therefore, drugs affecting the levels of 5HT in the synapse and in these pathways may lead to effective therapy of depression

Question 12

What are SSRIs?

Answer 12

By targeting the seratonin transporter (SERT) and inhibiting the reuptake of 5-HT to the presynaptic cells it is possible to increase the amount of 5HT in the synaptic cleft and avaialble to the postsynapse. This led to a development of compounds which bind more selectivily to seratonin transporter than other neurotransmitter receptors - these are known as SSRIs

Question 13

What are the goals of SSRI design?

Answer 13

• High affinity and selectivity for seratonin transporter
• Ability to inhibit seratonin transporter on binding
• Low affinity for multiple neauroreceptors known to be responsible for the side effects for tricyclic antidepressants
• No inhibition of the fast Na channels that cause cardiotoxicity issues with the tricyclics

Question 14

What are the properties of citaloporam as a SSRI?

Answer 14

• Has high affinity for the seratonin transporter
• Widely used for the treatment of depression
• 80% bioavaialibility
• 35 hour half life
• The S isomer of citalopram has the desired antidepressant effect - it has 27 times more affinity and twice as potent overall
• Citalopram is marketed as a racemic mixture but is now also manufactured as the pure S form - Escitalpram
• Mostly metabolised in the liver - CYP2C19, CYP3A4 and CYP2D6
• Has 1 chiral centre

Question 15

What is the structure activity relationship of SSRIs?

Answer 15

• SSRI all have a halogen or halogen bearing substituent on an aromatic ring - these appear to be important for SSRI activity profile and selectivity
• Paroxetine is one of the most potent SSRIs - it is a conformationally constarined analogue of fluoxetine where the linear phenylpropylamine is folded inyto a piperidine ring
• Talopram was first developed as an NE uptake inhibitor (SNRI) - due to suicidal rates in trials, it never made it to marked but it was modied as citalopran (SSRI). Citalopram is the 2nd most potent SSRI and escitalopram is the most selective SSRI for seratonin transporter