Heterodimerization of serotonin receptors 5-HT1A 5-HT and ...
5-HT Receptors and the Development of Sumatriptan
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Transcript of 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