Lecture 10 - development of treatments

Question 1

what are serotonergic receptors that have been identified ?

Answer 1

5-HT1 to 5-HT7

Question 2

what are drugs made to target for serotonergic neurotransmission and what are the 2 similarities detected to be targeted?

Answer 2

the serotonergic receptors . similarity between 5-HT and LSD

Question 3

what are atypical antipsychotics?

Answer 3

Olanzapine, risperidone and clozapine (also Amisulpride, Aripiprazole etc.

Olanzapine and clozapine are often referred to as belonging to the tricyclic antipsychotics (three fused rings)

5-HT2A Receptor antagonists
Also bind 5-HT2C (and dopamine receptors, hence “atypical” – more later)

Question 4

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

Answer 4

Role in thermoregulation and sleep

Could also be involved in appetite control (weight gain from clozapine and olanazapine – see later), learning and cardiovascular function and muscle contractions

5-HT2C antagonism could be useful in the treatment of anxiety, sleep and mood disorders

Question 5

what is the dopamine hypothesis in schizophrenia?

Answer 5

The dopamine hypothesis in schizophrenia
Arose from early observation of phenothiazines (chlorpromazine) and their effect on dopamine metabolism

The hypothesis being that schizophrenia results from increased dopaminergic neurotransmission

Approaches which decrease dopaminergic neurotransmission will alleviate psychotic symptoms

Most antipsychotic agents have activity to limit dopaminergic neurotransmission

It is believed that extrapyramidal side effects are reduced in drugs with less affinity for D2 receptors

Question 6

what are atypical antipsychotics for treating autism?

Answer 6

risperidone and aripiprazole.

Atypical antipsychotics are generally considered more effective than conventional antipsychotics for improving the negative symptoms of schizophrenia such as anhedonia, avolition, and apathy.

These negative symptoms have similarities to the social impairment characteristic of autism

Question 7

describe ADHD treatment drugs

Answer 7

Methylphenidate and dexamphetamine

In contrast to the antipsychotics, 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

describe methylphenidates pharmacological properties

Answer 8

Methylphenidate (Ritalin)
Cocaine-related agent – not structurally but in terms of pharmacological profile
Binds the DA transporter preventing the reuptake of DA

Methylphenidate contains two chiral centres at C2 and C2’
This means there are 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

describe dexamfetamine pharmacological properties

Answer 9

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

Question 10

what is the serotonin hypothesis of depression?

Answer 10

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 5-HT in the synapse and in these pathways may lead to effective therapy of depression

Question 11

describe SSRIs

Answer 11

By targeting serotonin transporter (SERT) and inhibiting the reuptake of 5-HT to the presynaptic cells it is possible to increase the amount of 5-HT in the synaptic cleft and available to the postsynapse
This thinking led to the development of a class of compounds which bind much more selectively to SERT rather than other NT receptors

These compounds became known as the SSRIs

Question 12

what are the goals of SSRI design?

Answer 12

High affinity and selectivity for SERT

Ability to inhibit SERT on binding

Low affinity for multiple neuroreceptors known to be responsible for the side effects of tricyclic antidepressants

No inhibition of the fast Na channels that cause cardiotoxicity issues with the tricyclics…

Question 13

describe the pharmacological properties of citalopram.

Answer 13

As with other SSRIs, citalopram has high affinity for SERT

The S isomer of citalopram has the desired antidepressant effect (~27x 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)

Question 14

what is the structure activity relationship of SSRIs?

Answer 14

SSRIs all have a halogen or halogen-bearing substituent on an aromatic ring
These appear to be important for SSRI activity profile and selectivity

Question 15

what is the most potent SSRI?

Answer 15

Paroxetine is one of the most potent SSRIs
Paroxetine is a conformationally constrained analogue of fluoxetine where the linear phenylpropylamine is folded into a piperidine ring

Question 16

describe talopram vs citalopram

Answer 16

Talopram was first developed as an NE uptake inhibitor (the SNRI family)
Due to suicides in trials it never made it to market but it was subsequently modified to be a SSRI – citalopram
Citalopram is the 2nd most potent SSRI and Escitalopram is the most selective SSRI for SERT

Question 17

summary of lecture

Answer 17

1 Affective and psychotic disorders are complicated and currently difficult to completely rationalise on a molecular basis

2 To better treat a disorder requires an understanding of the NTs involved and the mechanisms by which they are regulated. Structural data, which are now starting to become available, will help rationalise some of the existing chemistry

3 SAR have been developed for classes of compounds used to treat specific disease but optimisation for one can lead to off-target effects at other NT receptors along with any resulting side effects (discoveries in the area have often exploited these unexpected findings)

4 Important to consider that for many patients the longer term clinical benefits of different drugs is much the same (part of the neuropharmacology picture is missing…)