An Overview of the 5-HT7 Receptor

Andrew Marshall

Sep 1

Introduction

The 5-HT₇ receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT₇ receptor is coupled to G_s (stimulates the production of the intracellular signalling molecule cAMP) and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. This receptor has been a drug development target for the treatment of several clinical disorders. The 5-HT₇ receptor is encoded by the HTR7 gene, which in humans is transcribed into 3 different splice variants.

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 G_s from the GPCR complex. G_s 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 localised in enteric nerves; high levels of 5-HT₇ receptor-expressing mucosal nerve fibres 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-HT_7(a), h5-HT_7(b), and h5-HT_7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT_7(a) is the full length receptor (445 amino acids), while the h5-HT_7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT_7(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-HT_7(a). A 5-HT_7(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 characterised. 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. Signalling 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-HT_1A/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-HT_7(a) and h5-HT_7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT_7(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
Methysergide
Mianserin
Olanzapine
Pimozide
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

Inactivating Antagonists

Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitisation. Inactivation of the 5-HT₇ receptor, however, does not arise from the classically described mechanisms of receptor desensitisation 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 risperidone.

Bromocriptine
Lisuride
Metergoline
Methiothepin
Paliperidone
Risperidone

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/5-HT7_receptor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.