5-HT7 receptor

Function

When the 5-HT7 receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein Gs from the GPCR complex. Gs in turn activates adenylate cyclase which increases intracellular levels of the second messenger cAMP.

The 5-HT7 receptor plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract. The highest 5-HT7 receptor densities are in the thalamus and hypothalamus, and it is present at higher densities also in the hippocampus and cortex. The 5-HT7 receptor is involved in thermoregulation, circadian rhythm, learning and memory, and sleep. Peripheral 5-HT7 receptors are localized in enteric nerves; high levels of 5-HT7 receptor-expressing mucosal nerve fibers were observed in the colon of patients with irritable bowel syndrome. An essential role of 5-HT7 receptor in intestinal hyperalgesia was demonstrated in mouse models with visceral hypersensitivity, of which a novel 5-HT7 receptor antagonist administered perorally reduced intestinal pain levels. It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.

Variants

Three splice variants have been identified in humans (designated h5-HT7(a), h5-HT7(b), and h5-HT7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT7(a) is the full length receptor (445 amino acids), while the h5-HT7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT7(d) is a distinct isoform of the receptor: the retention of an exon cassette in the region encoding the carboxyl terminal results a 479-amino acid receptor with a c-terminus markedly different from the h5-HT7(a). A 5-HT7(c) splice variant is detectable in rat tissue but is not expressed in humans. Conversely, rats do not express a splice variant homologous to the h5-HT7(d), as the rat 5-HT7 gene lacks the exon necessary to encode this isoform. Drug binding affinities are similar across the three human splice variants; however, inverse agonist efficacies appear to differ between the splice variants.

Discovery

In 1983, evidence for a 5-HT1-like receptor was first found. Ten years later, 5-HT7 receptor was cloned and characterized. It has since become clear that the receptor described in 1983 is 5-HT7.

Ligands

Numerous orthosteric ligands of moderate to high affinity are known. Signaling biased ligands were discovered and developed in 2018.

Agonists

Agonists mimic the effects of the endogenous ligand, which is serotonin at the 5-HT7 receptor (↑cAMP).

• 5-Carboxamidotryptamine (5-CT)
• 5-methoxytryptamine (5-MT, 5-MeOT)
• 8-OH-DPAT (mixed 5-HT1A/5-HT7 agonist)
• Aripiprazole (weak partial agonist)
• AS-19
• E-55888
• E-57431
• LP-12 (4-(2-Diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide)
• LP-44 (4-[2-(Methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide)
• LP-211
• MSD-5a
• Nω-Methylserotonin
• N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides (can function as either an agonist or antagonist depending on side chain substitution)
• N,N-Dimethyltryptamine
• AGH-107 (water-soluble, brain penetrating full agonist)
• AH-494 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide)
• AGH-192 (orally bioavailable, water-soluble, brain penetrating full agonist)

Antagonists

Neutral antagonists (also known as silent antagonists) bind the receptor and have no intrinsic activity but will block the activity of agonists or inverse agonists. Inverse agonists inhibit the constitutive activity of the receptor, producing functional effects opposite to those of agonists (at the 5-HT7 receptor: ↓cAMP). Neutral antagonists and inverse agonists are typically referred to collectively as "antagonists" and, in the case of the 5-HT7 receptor, differentiation between neutral antagonists and inverse agonists is problematic due to differing levels of inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT7(a) and h5-HT7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT7(b) splice variant.

• 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one
• Amisulpride
• Amitriptyline
• Amoxapine
• Brexpiprazole
• Clomipramine
• Clozapine
• CYY1005 (a highly selective, orally active 5-HT7 antagonist)
• DR-4485
• EGIS-12233 (mixed 5-HT6/5-HT7 antagonist)
• AVN-101 (mixed 5-HT6/5-HT7 antagonist)
• Fluphenazine
• Fluperlapine
• ICI 169,369
• Imipramine
• JNJ-18038683
• Ketanserin
• Loxapine
• Lurasidone
• LY-215,840
• Maprotiline
• Mesulergine
• Metitepine
• Methysergide
• Mianserin
• Nuciferine
• Olanzapine
• Pimozide
• Pirepemat
• RA-7 (1-(2-diphenyl)piperazine)
• Ritanserin
• SB-258,719
• SB-258741
• SB-269970 (highly 5-HT7 selective)
• SB-656104-A
• SB-691673
• Sertindole
• Spiperone
• Tenilapine
• TFMPP
• Vortioxetine
• Trifluoperazine
• Ziprasidone
• Zotepine

Tetrahydroisoquinoline alkaloids found in peyote and related to mescaline have been found to act as potent inverse agonists of the serotonin 5-HT7 receptor. These compounds include pellotine, anhalidine, anhalonidine, anhalamine, and N-methylanhalinine.

Inactivating antagonists

Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitization. Inactivation of the 5-HT7 receptor, however, does not arise from the classically described mechanisms of receptor desensitization via receptor phosphorylation, beta-arrestin recruitment, and receptor internalization. Inactivating antagonists all likely interact with the 5-HT7 receptor in an irreversible/pseudo-irreversible manner, as is the case with [3H]risperidone.

• Bromocriptine
• Lisuride
• Metergoline
• Methiothepin
• Paliperidone
• Risperidone

References

References

1. (February 2000). "5-HT7 receptors: current knowledge and future prospects". Trends in Pharmacological Sciences.
2. (September 1993). "Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation". Proceedings of the National Academy of Sciences of the United States of America.
3. (November 1993). "Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase". The Journal of Biological Chemistry.
4. (December 2007). "5-HT7 receptor antagonists as a new class of antidepressants". Drug News & Perspectives.
5. (April 1997). "Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization". Journal of Neurochemistry.
6. (2022). "5-HT 7 receptor-dependent intestinal neurite outgrowth contributes to visceral hypersensitivity in irritable bowel syndrome". Laboratory Investigation.
7. (September 2004). "Functional, molecular and pharmacological advances in 5-HT7 receptor research". Trends in Pharmacological Sciences.
8. (July 2014). "Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders". CNS Neuroscience & Therapeutics.
9. (June 2001). "The cloned human 5-HT7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution". Naunyn-Schmiedeberg's Archives of Pharmacology.
10. (March 2002). "The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects". British Journal of Pharmacology.
11. (December 1983). "5-Hydroxytryptamine-induced relaxation of isolated mammalian smooth muscle". European Journal of Pharmacology.
12. (April 2002). "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacology Biochemistry and Behavior.
13. (August 2018). "Discovery of β-Arrestin Biased Ligands of 5-HT7R". J. Med. Chem..
14. (January 2004). "8-OH-DPAT as a 5-HT7 agonist: phase shifts of the circadian biological clock through increases in cAMP production". Neuropharmacology.
15. Davies MA, Sheffler DJ, [[Bryan Roth. Roth BL]]. Aripiprazole: A Novel Atypical Antipsychotic Drug With a Uniquely Robust Pharmacology. CNS Drug Reviews [Internet]. 2004 [cited 2013 Aug 4];10(4):317–36. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00030.x/pdf
16. (August 2011). "Potentiation of morphine analgesia by adjuvant activation of 5-HT7 receptors". Journal of Pharmacological Sciences.
17. (June 2010). "Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity". Pain.
18. (February 2009). "5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice". Pain.
19. (December 2008). "In vitro serotonergic activity of black cohosh and identification of N(omega)-methylserotonin as a potential active constituent". Journal of Agricultural and Food Chemistry.
20. (August 2007). "Structure-activity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a class of 5-HT7 receptor agents. 2". Journal of Medicinal Chemistry.
21. (December 2004). "Structure-affinity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides, a new class of 5-hydroxytryptamine7 receptor agents". Journal of Medicinal Chemistry.
22. (May 2017). "Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol". Scientific Reports.
23. (September 2018). "Search for a 5-CT alternative. In vitro and in vivo evaluation of novel pharmacological tools: 3-(1-alkyl-1H-imidazol-5-yl)-1H-indole-5-carboxamides, low-basicity 5-HT7 receptor agonists.". MedChemComm.
24. (2019). "Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers". European Journal of Medicinal Chemistry.
25. (September 2007). "5-HT7 receptor ligands: recent developments and potential therapeutic applications". Mini Reviews in Medicinal Chemistry.
26. (March 2004). "Serotonin(7) receptors (5-HT(7)Rs) and their ligands". Current Medicinal Chemistry.
27. (April 2008). "(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists". Journal of Medicinal Chemistry.
28. (July 2009). "Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo". Psychopharmacology.
29. (2016). "AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders.". J. Alzheimer's Dis..
30. (2012). "Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin7 (5-HT7) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo". Journal of Medicinal Chemistry.
31. (February 1998). "(R)-3,N-dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl) propyl]benzenesulfonamide: the first selective 5-HT7 receptor antagonist". Journal of Medicinal Chemistry.
32. (July 2004). "Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors". European Journal of Pharmacology.
33. (February 2000). "A novel, potent, and selective 5-HT(7) antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl) phen ol (SB-269970)". Journal of Medicinal Chemistry.
34. (November 2002). "SB-656104-A: a novel 5-HT(7) receptor antagonist with improved in vivo properties". Bioorganic & Medicinal Chemistry Letters.
35. (October 2006). "Reanalysis of constitutively active rat and human 5-HT7(a) receptors in HEK-293F cells demonstrates lack of silent properties for reported neutral antagonists". Naunyn-Schmiedeberg's Archives of Pharmacology.
36. (February 2025). "Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists". ACS Chem Neurosci.
37. (1997). "Molecular mechanisms of G protein-coupled receptor signaling: role of G protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization". Receptors & Channels.
38. (October 2006). "Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor". Molecular Pharmacology.
39. (February 2009). "Pharmacological analysis of the novel, rapid, and potent inactivation of the human 5-Hydroxytryptamine7 receptor by risperidone, 9-OH-Risperidone, and other inactivating antagonists". Molecular Pharmacology.