structural approach to serotonergic drugs

1. Serotonin; receptors, function
and chemistry
Saman Arab

2. Structure, biosynthesis and
metabolism
• structure

3. biosynthesis

4. metabolism

5. receptors

6. Non selective serotonin agonists
• Tryptamines
• Lysergamides
• Phenethylamines
• amphetamines

7. tryptamines
• Psilocybin • psilocin

8. • N,N-dimethyltryptamine
(DMT)
• 5-MeO-DMT

9. bufotenin

10. lysergamides
• LSD • LSA (ergine)

11. Phenethylamines
• mescaline

12. Amphetamines
• MDA • DOM

13. 5-HT1 receptor agonists

14. 5-HT1A receptor agonists
• Azapirones
• Antidepressants
• Atypical antipsychotics

15. Azapirones
• 5-HT1A receptor partial agonists marketed
primarily as anxiolytics, but also as
antidepressants.

16. • buspirone • gepirone

17. • tandospirone • perospirone

18. antidepressants
Long chain aryl piperazines
• Vilazodone
• Trazodone
• nefazodone

19. Atypical antipsychotics (partial
agonist)
• Aripiperazole
• brexpiperazole

21. 5-HT1B receptor agonists
• Phenylpiperazines
• Triptanes
• ergotamine

22. Phenylpiperazines (5-HT1A and 5-HT1B
receptor agonist)
• Eltoprazine
• Batoprazine
• fluprazine

23. Triptanes (types 5-HT1D and 5-HT1B)
• Sumatriptane
• Naratriptane
• Rizatriptane
• Zolmitriptane

24. ergotamine
• shares structural similarity
with neurotransmitters such
as serotonin, dopamine, and
epinephrine and can thus bind
to several receptors acting as
an agonist. The anti-migraine
effect is due to constriction of
the intracranial extracerebral
blood vessels through the 5-
HT1B receptor, and by
inhibiting trigeminal
neurotransmission by 5-HT1D
receptors.

25. 5-HT1E receptor agonists
• eletriptan is an agonist of the
5-HT1E receptor. BRL-54443 is
a selective 5-HT1E and 5-HT1F
receptor agonist which is used
in scientific research.
• Eletriptane
• BRL-54443

26. 5-HT1F receptor agonists
• Triptans such as eletriptan,
naratriptan, and sumatriptan
are agonists of the 5-HT1F
receptor. Lasmiditan is a
selective 5-HT1F agonist that is
under development by Eli Lilly
and Company for the
treatment of migraine

27. 5-HT2 receptor agonists

28. 5-HT2A receptor agonists
• Discussed in non selective 5HT agonists.

29. 5-HT2B receptor agonists
• Agonists of the 5-HT2B receptor are implicated in
the development of cardiac fibrosis.
Fenfluramine, pergolide, and cabergoline have
been withdrawn from some markets for this
reason. Many serotonergic psychedelics, such as
LSD and psilocin, have been shown to activate
this receptor directly. MDMA has been reported
to be both a potent direct agonist and have an
indirect effect by increasing plasma serotonin
levels.

30. • Fenfluramine
• Pergolide
• cabergoline

31. 5-HT2C receptor agonists
• Lorcaserin is an appetite
suppressant and anti-obesity
drug which acts as a selective
5-HT2C receptor agonist. meta-
Chlorophenylpiperazine
(mCPP) is a 5-HT2C-preferring
serotonin receptor agonist that
induces anxiety and
depression and can cause
panic attacks in susceptible
individuals.
• Lorcaserin
• mCPP

32. 5-HT3 receptor agonists
• 2-Methyl-5-
hydroxytryptamine (2-
methylserotonin) and
quipazine are moderately
selective agonists of the 5-HT3
receptor that are used in
scientific research. Agonists of
this receptor are known to
induce nausea and vomiting,
and are not used medically.
• 2-methylserotonin (sel. Ful.
Ag.)
• quipazine

33. 5-HT4 receptor agonists
• Cisapride and tegaserod are 5-
HT4 receptor partial agonists
that were used to treat
disorders of gastrointestinal
motility. Prucalopride is a
highly selective 5-HT4 receptor
agonist that can be used to
treat certain disorders of
gastrointestinal motility. Other
5-HT4 receptor agonists have
shown potential to be
nootropic and antidepressant
drugs, but have not been
marketed for such indications.
• Cisapride
• Prucalopride

34. • Tegaserod
management of irritable bowel
syndrome and constipation.
Approved by the FDA in 2002,
it was subsequently removed
from the market in 2007 due
to FDA concerns about
possible adverse
cardiovascular effects

35. 5-HT5A receptor agonists
• Valerenic acid, a constituent of
valerian root, has been found
to act as a 5-HT5A receptor
agonist, and this action could
be involved in the sleep-
promoting effects of valerian.

36. 5-HT6 receptor agonists
• No selective agonists of the 5-
HT6 receptor have been
approved for medical use.
• Selective 5-HT6 receptor
agonist EMDT, shows
antidepressant, anxiolytic,
antiobsessional, and appetite
suppressant effects in animals,
but also impair cognition and
memory.
• EMDT

37. 5-HT7 receptor agonists
• AS-19 is a 5-HT7 receptor
agonist that has been used in
scientific research.
• It reverses the amnesia
induced by drugs such as
scopolamine and dizocilpine
and improves long term
memory acquisition, but
inhibits short term memory
formation.

38. Serotonin receptor antagonists

39. 5-HT2A antagonists
• Cyproheptadine blocks 5-HT2A, H1 and is a mild
anticholinergic.

40. • Quetiapine blocks 5-HT2A, 5-HT1A, dopamine
receptors D1 and D2, histamine receptor H1, and
A1 adrenoreceptors.

41. • Methysergide is a 5-HT2A antagonist and
nonselective 5-HT1 receptor blocker.

42. 5-HT2A/2C antagonists

43. • trazodone • Nefazodone (primarily
5HT2A)

44. • Ketanserin Antihypertensive.
Blocks 5-HT2A, 5-HT2C and
Alpha 1 (A1) adrenoreceptors.
• With tritium (3H) radioactively
labeled ketanserin is used as a
radioligand for serotonin 5-HT2
receptors, e.g. in receptor
binding assays and
autoradiography. This radio-
labeling has enabled the study of
serotonin 5-HT2A receptor
distribution in the human brain.
• Ki values of 2–3 nM for the 5-
HT2Areceptor and 130 nM for
the 5-HT2C receptor

45. 5-HT3 antagonists
• 5-HT3 antagonists are efficacious in treating
chemotherapy-induced emesis and
postoperative nausea and vomiting.

46. derivatives of Indole-3-carboxilic acid
ester analogues
• Ondansetron
• granisetrone
• Tropisetrone
• dolasetrone

47. • Alosetrone and cilansetrone
are used for the treatment of
IBS
• Alosetrone
• Cilansetrone

48. Other serotonin inhibitors
• Fenclonine (para-
chlorophenylalanine; PCPA)
An inhibitor of serotonin
synthesis that has been used in
the treatment of carcinoid
syndrome.
• Reserpine antipsychotic, and
antihypertensive drug that has
been used for the control of
high blood pressure and for
the relief of psychotic
symptoms. Depletes serotonin
stores.