5-ht receptors and the development of sumatriptan

8/11/2019 5-HT Receptors and the Development of Sumatriptan

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5-HT Receptors and the Development of

Sumatriptan from Serotonin

Role of 5-HT in Migraine

Discovery of Sumatriptan


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MigraineMigraine

Affects approx. 10% of adult population.

Approx. one third of all sufferers experience 2 ormore attacks per month.

Attacks can last up to three days. Headache phase of migraine is associated with

vasodilatation of certain pain-sensitive bloodvessels located in the head.

Rationale was to achieve selectivevasoconstriction of the pain sensitive bloodvessels in the head.


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Biogenic amine biosynthesised from tryptophan

Blood platelet 5-HT levels fall by up to 40% at onset of

migraine

5-HT will abort an established migraine when administered i.v.

5-Hydroxytriptamine and migraine

NH

COOH

NH2

NH

NH2HO

Tryptophane 5-Hydroxytryptamine

(Serotonin)


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5-HT receptor subtypes andtheir localisation

Subtype Main localisation

1A CNS

1B CNS, Vascular smooth muscle

1D CNS,Cerebral blood vessels

2A CNS, PNS, Smooth muscle, platelets

2B Gastric Fundus

2C CNS, chorioid plexus

3 PNS, CNS

4 PNS (GI tract), CNS

5 CNS

6 CNS

7 CNS, GI tract, blood vessels


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Bio assays with 5-HT as agonist

Receptor subtype Preparation Parameter

5-HT1 Dog Safenous Vein Vasoconstriction

5-HT2 Rabbit aorta Contraction

5-HT3 Rat vagus nerve Depolarisation


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5-CT : 5-HT1 receptor selective lead compound

more potent than 5-HT at 5-HT1 receptor

less potent than 5-HT at the 5-HT2 receptor

NH

NH2

H2N

O

5-Carboxamidotryptamine (5-CT)

NH

COOH

NH2

NH

NH2HO

Tryptophane5-Hydroxytryptamine

(Serotonin)

Reminder


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The best

N

H

NH2HN

O

Methylene introduced between theindole ring and the carboxamide.

17


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N-methylcarboxamide (17) [AH25086]possessed best i n v i t r o profile

Became leading candidate for progression

Produced vasoconstriction in carotid arterial bedof anaesthetised dog when administered i.v.

Little effect on BP, heart rate or total peripheralresistance.

Tolerated in human volunteers.

Effective in alleviating symptoms of acutemigraine attack when administered i.v.

However: Poor oral availability.


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Wanted compound suitable for oral and

parenteral administration

Two paths followed

Explore sulfonamide structures instead of

carboxamide in attempt to increase oral

bioavailability

Explore alternatives to primary amino group,in attempt to inhibit its metabolism.

Discovery of Sumatriptan


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Development of Sulphonamides


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Methylamino (25) and dimethylamino (26) displayedenhancement of agonist potency.

Selected amino derivatives


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Compound 26: [GR43175]

Caused selective carotid vasoconstriction in anaesthetiseddogs viaboth i.v. and intraduodenal routes

Displayed remarkable selectivity for the DSV 5-HT1-likereceptor sub-type, being devoid of activity at 5-HT2 , 5-HT3 , Adrenergic, Dopaminergic, Muscarinic, Benzodiazepine receptors

Molecular studies showed that it acted on 5-HT1Dreceptors

Named Sumatriptan and progressed through fulldevelopment

NH

N

S

HN

O

O


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Sumatriptan

Launched under the trade name Imigran in June 1991as a novel therapy for the acute treatment of migraine

Sumatriptan alleviated not only the pain of migrainebut also the associated symptoms of nausea, vomiting

and photophobia You can buy sumatriptan over the counter (very

expensive)

However, reported side-effects of chest pain andtightness (coronary vasoconstriction) have promptedthe advice that Sumatriptan should not be used inpatients with ischaemic heart disease, angina oruncontrolled hypertension.


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The me-too triptans

Pharmaceutical companies began to lookfor new antimigraine agents to repeat andhopefully improve on the success ofSumatriptan

Almotriptan, Eletriptan, Frovatriptan,Naratriptan, Rizatriptan, Zolmitriptan

5-HT1Dagonists

Fewer side effects than sumatriptan

Improved bioavailability and duration ofaction

5-ht receptors and the development of sumatriptan

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