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In Drug Discovery

Everything we know about the 5-HT1B receptor

By Zara Puckrin, BSc / 21 April 2022


Looking for a comprehensive guide to the serotonin 5-HT1B receptor? In this article, we'll give you a breakdown of everything scientists know so far about the molecular structure, physiology, and pharmacology of this serotonin receptor. 


What do we know about the 5-HT1B receptor?

The 5-HT1B receptor is a G0-coupled protein receptor with seven transmembrane domains - one of which is a ligand-binding site.1 Located primarily in the central nervous and vascular tissues2, there is evidence that the 5-HT1B receptor regulates a range of neurological, physiological, and pathological processes, including addiction3, migraine1, and sleep.4

These receptors are found on the axon of presynaptic neurons in the frontal cortex, basal ganglia, and retro-medial dorsal raphe nucleus.5 As their name suggests, they control 5-HT (serotonin) release in serotonergic neurons, where they act as inhibitory auto-receptors.2 They are also present in non-serotonergic neurons, where they act as heteroreceptors, inhibiting the release of acetylcholine, glutamate, GABA, and noradrenaline.5

Due to the range of neurotransmitters controlled by 5-HT1B, it is associated with a range of neurological functions, including mood, memory, aggression, stress sensibility, and anxiety.1 It is also present in the "extended amygdala" of the brain, a reward circuit associated with drug reinforcement.1 It is, therefore, unsurprising that variations in the 5-HT1B gene have been associated with addiction and obsessive-compulsive disorder in humans.3 

The 5-HT1B receptor is also present in the cardiovascular system, with high concentrations in the cerebral arteries6. Here 5-HT1B receptor activation leads to vasoconstriction, which may be beneficial to the treatment of migraine. Its expression in other arteries, such as coronary arteries, means that consideration must however be given to the potential for adverse cardiovascular effects. 5-HT1B also mediates inhibition of plasma extravasation, where fluid leaks from blood vessels into the surrounding tissues.6

Cardiac effects of 5-HT1B

Activation of  5-HT1B receptors can cause vasoconstriction in coronary arteries, which can lead to myocardial infarction in patients with underlying cardiovascular conditions.7 Some 5-HT1B receptors have been described as “silent”, requiring a vessel to be primed with a de-polarising stimulus, such as high K+ before a functional receptor is observed.8 This pharmacologically synergistic mechanism, known as “demasking”, can make predicting how a specific agonist will affect the cardiovascular system challenging and highlights the need for more predictive testing.

5-HT (serotonin) model
This assay uses subcutaneous resistance arteries to assess the effect of your test article on vasoconstriction via 5-HT (serotonin) receptors.


What is the difference between 5-HT1B and 5-HT1D?

Not only are the 5-HT1B and 5-HT1D receptors co-expressed, but they share a similar affinity for many drugs. Previously, they were thought to be the same receptor, but they are now understood to be different subtypes in humans.5 There is only one known agonist that can select between 5-HT1B and 5-HT1D, and only a handful of antagonists (table 1).5 It is thought that therapeutics, such as anti-migraine drugs, bind to both subtypes to exert their therapeutic effects, which has made distinguishing these receptors more complicated.5

Drug Agonist or Antagonist 5-HT1B pKB
L694247 Agonist 10.0
GR55562 Antagonist 7.4
SB224289 Antagonist 8.5
SB236657 Antagonist 8.9
SB236057 Antagonist 8.9

Table 1: A list of selective 5-HT1B drugs and their binding affinity (pKB).


What was the first therapeutically used serotonin 5-HT1 receptor agonist?

Sumatriptan (dihydroergotamine, DHE) was the first 5-HT1B agonist to be used therapeutically.5 It now belongs to a wider group of drugs known as the triptans, which include almotriptan, zolmitriptan, and naratriptan.6 Triptans are non-selective blockers of the 5-HT1 receptors that are commonly used to treat migraine.5 While sumatriptan has a higher affinity for the 5-HT1D subtype than 5HT1B it has a low selectivity for other receptors, making it a highly targeted 5-HT1 agonist.5

Despite these drugs being widely prescribed for migraine, it is still unclear how they exert their therapeutic effects.5 So far, they are either thought to block neurogenic inflammation and nociceptive activity, or constriction-mediate 5-HT1B receptors on the cerebral arteries to reduce the symptoms of migraine.5

5-HT (serotonin) receptors in denuded arteries
This model assesses the effect of your test article on vasoconstriction of denuded arteries via 5-HT (serotonin) receptors, in comparison to 5-HT (serotonin).

5-HT (serotonin) receptors and 5-HT
This model assesses the effect of your test article on vasoconstriction via 5-HT (serotonin) receptors, or in comparison to 5-HT (serotonin).


Are there species differences between 5HT1B/1D?

Our understanding of 5-HT1B/1D receptor function across different species has much room for progress. Despite the structure of the human 5-HT1B receptor being homologous to that in rats, differences in pharmacological response exist between rodents and humans.5 These differences are thought to be caused by a single amino acid change in the transmembrane region (Thr335 is replaced by Asn in rodents) which was discovered due to differences in the binding affinity of cyanopindolol.5

However, these species differences do not only exist between animals and humans but also among closely related species. For example, 5-HT1B activation leads to hyperlocomotion in mice and hypothermia in guinea pigs but not rats.5 And while there is evidence that hypophagia and penile erection are mediated by the 5-HT1B receptor in rats, this is yet to be characterized in other rodents.5 Our limited knowledge of 5-HT1B receptor function across different species supports the philosophy that animal research should be reduced, refined, and replaced by more translational alternatives wherever possible. 


What are the benefits of testing a 5HT1B/1D agonist in human tissue?

When the 5-HT1B agonist sumatriptan was first tested in humans, one of the volunteers experienced a cardiac event in response to intravenous administration. To investigate this off-target response, the researchers decided to look at the effect of the drug on artery tone ex vivo.9 Using human coronary arteries, they discovered that 5-HT had a larger effect on coronary artery tone than sumatriptan which had a minimal effect.9  Researchers, therefore, decided to continue the clinical trial, and today sumatriptan is considered safe for the treatment of migraine in patients without cardiovascular contraindications.7

5-HT (serotonin) receptors and sumatriptan
This model assesses the effect of your test article on coronary artery tone using sumatriptan as a reference compound.

 

 

 


Where can I outsource human tissue testing for 5-HT1B agonists?

If you are looking to improve the translatability of your drug discovery research, human tissue testing allows you to look at human data before testing your compound in the clinic. It can even be used to compare drug responses between animals and humans to investigate off-target drug effects on cardiovascular tissues. At REPROCELL, our scientists can test the effects of your compound on human blood vessels. You can find examples of our work listed in our assay catalog or contact us to arrange a custom solution for your research needs

Examples of previous studies investigating the effects of 5-HT on cardiac tissue are listed below:

CTA-Cardiovascular tissues


References 

  1. Sari Y et al. The Brain as a Drug Target. Progress in Molecular Biology and Translational Science 98 pp 401-433 (2011).
  2. Sharma H.S. Influence of Serotonin on the Blood-Brain and the Blood-Spinal Cord Barriers. Blood and Spinal Cord Barriers in Health and Disease (2004).
  3. Meneses A. 5-HT1B Receptor. The Role of 5-HT Systems on Memory and Dysfunctional Memory (2014).
  4. Nonogaki K. Sleep Hormones. Vitamins and Hormones 89 pp 1-17 (2012). 
  5. Blackburn T.P. Serotonin (5-Hydroxytryptamine; 5-HT): Receptors. Encyclopedia of Neuroscience (2009).
  6. Hoyer D. 5-HT-1B Receptor. xPharm: The Comprehensive Pharmacology Reference (2007). 
  7. Abbrescia VD, Pearlstein L, Kotler M. Sumatriptan-associated myocardial infarction: report of case with attention to potential risk factors. J Am Osteopath Assoc. 97(3), 162-164. (1997)
  8. Yildiz, O., Smith, J. R., & Purdy, R. E. Serotonin and vasoconstrictor synergismLife sciences62(19), 1723–1732. (1998)
  9. Tansey EM & Yabsley A. Humphrey, Patrick: 04 - Sumatriptan: safety issues. History of Modern Biomedicine Interviews (Digital Collection) Item e2016025 (2016)

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