5-HT1D receptor

Tissue distribution

5HT1D receptors are found at low levels in the basal ganglia (globus pallidus, substantia nigra, caudate putamen), the hippocampus, and in the cortex.

Structure

5HT1D receptor is a G protein linked receptor that activates an intracellular messenger cascade to produce an inhibitory response by decreasing cellular levels of cAMP. The 5HT1D is a 7-TM receptor. A large intercellular loop between TM-5 and TM-6 is believed to be associated with coupling to a second messenger. Agonists might bind in a manner that utilizes an aspartate residue in TM-3 and residues in the TM-4, TM-5 and TM-6. A human clone containing an intronless open reading frame was found to encode 377 amino acids of the 5HT1D receptor. The gene has been localized on chromosome 1, region 1p34.3-36.3

Ligands

Agonists

Molecular modelling has provided a picture of the agonistic binding site of 5HT1D. The amino acid residues within the receptor binding site region have been identified. This is a valuable guide to design potential 5HT1D receptor agonists. When sumatriptan binds there is major conformational change in both ligand and receptor in the binding pocket.

• 5-(Nonyloxy)tryptamine
• Sumatriptan (vasoconstrictor in migraine)
• Ergotamine (vasoconstrictor in migraine)
• Zolmitriptan
• 5-Carboxamidotryptamine (5-CT)
• 5-(t-Butyl)-N-methyltryptamine
• CP-135807
• CP-286601
• PNU-109291 ((S)-3,4-Dihydro-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-1H-2-benzopyran-6-carboxamide)
• PNU-142633 ((1S)-1-[2-[4-[4-(Aminocarbonyl)phenyl]-1-piperazinyl]ethyl]-3,4-dihydro-N-methyl-1H-2-benzopyran-6-carboxamide)
• GR-46611 (3-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide)
• L-694247 (2-[5-[3-(4-Methylsulfonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3-yl]ethanamine)
• L-760790
• L-772405
• PGI-7043

Antagonists

• Ziprasidone (atypical antipsychotic) https://books.google.com/books?id=HkA0Q31YDhAC&dq=antipsychotics+5ht1d&pg=PA438
• Methiothepin (antipsychotic)
• Yohimbine (aphrodisiac)
• Metergoline
• BRL-15572
• Vortioxetine (antidepressant)
• F-14258
• GR-127935 (mixed 5-HT1B/1D antagonist)
• LY-310762
• LY-367642
• LY-456219
• LY-456220

Negative allosteric modulators

• 5-HT-moduline

References

References

1. "Entrez Gene: HTR1D 5-hydroxytryptamine (serotonin) receptor 1D".
2. (2019). "The Serotonin System: History, Neuropharmacology, and Pathology". Academic Press.
3. (September 2008). "Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions". Trends in Pharmacological Sciences.
4. (1998). "Serotonin 5-HT_1B/1D Receptor Agonists in Migraine: Comparative Pharmacology and Its Therapeutic Implications". CNS Drugs.
5. (2013). "Foye's Principles of Medicinal Chemistry". Wolters Kluwer Health/Lippincott Williams & Wilkins.
6. (March 1992). "Characterization of the human 5-hydroxytryptamine1B receptor". The Journal of Biological Chemistry.
7. (April 1992). "Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta". Proceedings of the National Academy of Sciences of the United States of America.
8. (1997). "Modeling of the agonist binding site of serotonin human 5-HT_1A, 5-HT_1Dα and 5-HT_1Dβ receptors". European Journal of Medicinal Chemistry.
9. (September 1994). "5-(Nonyloxy)tryptamine: a novel high-affinity 5-HT1D beta serotonin receptor agonist". Journal of Medicinal Chemistry.
10. (February 1999). "N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist". Journal of Medicinal Chemistry.