Skip to main content

How selective is GR 43175? Interactions with functional 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors

Naunyn-Schmiedeberg's Archives of Pharmacology volume 340, pages 135–138 (1989)Cite this article

Summary

GR 43175 (3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5 methane sulphonamide) is a novel 5-HT1-like receptor-selective agonist which was reported to be active in the treatment of migraine attacks. The effects of the compound were investigated in radioligand binding studies and in functional models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphate production in pig choroid plexus).

GR 43175 displayed the following order of affinity for 5-HT recognition sites (pKD values, -log mol/l, in parentheses): 5-HT1D (7.54) > 5-HT1B (6.35) > 5-HT1A (6.13) ≫ 5-HT1C (4.13) > 5-HT2 (3.67). The same order of potency was observed at functional 5-HT1 receptors, at which GR 43175 acted as a full agonist, with the exception of the 5-HT1C receptor, where the compound was a weak antagonist (pEC50 or pKB values, -log mol/l, in parentheses): 5-HT1D (6.28) > 5-HT1B (6.03) > 5-HT1A (5.57) > 5-HT1C (4.25).

The present data show that GR 43175 interacts preferentially as an agonist with 5-HT1B and 5-HT1D receptors. Since 5-HT1B receptors have not yet been identified in human brain, it seems possible that it is the 5-HT1D receptor which is relevant to the reported antimigraine effects of this compound.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  • Bouhelal R, Smounya L, Bockaert J (1988) 5-HT1B receptors are negatively coupled with adenylate cyclase in rat substantia nigra. Eur J Pharmacol 151:189–196

    Google Scholar 

  • Bradley PB, Engel G, Feniuk W, Fozard JR, Humphrey PPA, Middlemiss DN, Mylecharane EJ, Richardson BP, Saxena PR (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 25:563–576

    Google Scholar 

  • Connor HE, Feniuk W, Humphrey PPA (1989) Characterization of 5-HT receptors mediating contraction of canine and primate basilar artery by use of GR 43175, a selective 5-HT1-like receptor agonist. Br J Pharmacol 96:379–387

    Google Scholar 

  • De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem 255:7108–7117

    Google Scholar 

  • Doenicke A, Brand J, Perrin VL (1988) Possible benefit of GR 43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. The Lancet I 8598:1309–1311

    Google Scholar 

  • Feniuk W, Humphrey PPA, Perren MJ (1987) Selective vasoconstrictor action of GR 43175 on arteriovenous anastomoses in the anaesthetised cat. Br J Pharmacol 92:756P

    Google Scholar 

  • Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muscholl E (eds) Catecholamines. Springer, Berlin Heidelberg New York Tokyo, pp 283–335

    Google Scholar 

  • Galzin AM, Blier P, Chodkiewicz JP, Poirier MF, Loo H, Roux FX, Rendondo A, Lista A, Ramdine R, Langer SZ (1988) Pharmacological characterization of the serotonin 5-HT autoreceptor modulating the electrically-evoked release of 3H-5-HT from slices of human frontal cortex. Soc Neurosci Abstr 14:129.7

    Google Scholar 

  • Heuring RE, Schlegel JR, Peroutka SJ (1986) Species variations in RU 24969 interactions with non-5-HT1A binding sites. Eur J Pharmacol 122:279–282

    Google Scholar 

  • Hoyer, D (1988) Molecular pharmacology and biology of 5-HT1C receptors. TIPS 9:89–94

    Google Scholar 

  • Hoyer D (1989) Biochemical mechanisms of 5-HT receptor-effector coupling in peripheral tissues. In: Fozard JR (ed) Peripheral actions of 5-HT. Oxford University Press, Oxford, pp 72–99

    Google Scholar 

  • Hoyer D, Engel G, Kalkman HO (1985) Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin. Eur J Pharmacol 118:13–23

    Google Scholar 

  • Hoyer D, Pazos A, Probst A, Palacios JM (1986) Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Res 376:85–96

    Google Scholar 

  • Hoyer D, Waeber C, Schoeffter P, Palacios JM, Dravid A (1989) 5-HT1C receptor-mediated stimulation of inositol phosphate production in pig choroid plexus; a pharmacological charac-terization. Naunyn-Schmiedeberg's Arch Pharmacol 339:252–258

    Google Scholar 

  • Humphrey PPA, Feniuk W, Perren MJ, Connor HE, Oxford AW, Coates IH, Butina D (1988) GR 43175 — A selective agonist for the 5-HT1-like receptors in dog isolated saphenous vein. Br J Pharmacol 94:1123–1132

    Google Scholar 

  • Middlemiss DN, Bremer ME, Smith SM (1988) A pharmacological analysis of the 5-HT receptors mediating inhibition of 5-HT release in the guinea-pig frontal cortex. Eur J Pharmacol 157:101–107

    Google Scholar 

  • Peroutka SJ (1988) 5-Hydroxytryptamine receptor subtypes. Ann Rev Neurosci 11:45–60

    Google Scholar 

  • Schipper J, Tulp MTM (1988) Serotonin autoreceptors in guinea pig cortex slices resemble the 5-HT1D binding site. Soc Neurosci Abstr 14:221.8

    Google Scholar 

  • Schlicker E, Fink K, Betz R, Göthert M (1988) The serotonin autoreceptor in the pig brain cortex belongs to the 5-HT1D receptor subtype. Naunyn-Schmiedeberg's Arch Pharmacol 338:(suppl) R67

    Google Scholar 

  • Schoeffter P, Hoyer D (1988) Centrally acting hypotensive agents with affinity to 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus. Br J Pharmacol 95:975–985

    Google Scholar 

  • Schoeffter P, Waeber C, Palacios JM, Hoyer D (1988) The serotonin 5-HT1D receptor subtype is negatively coupled to adenylate cyclase in calf substantia nigra. Naunyn-Schmiedeberg's Arch Pharmacol 337:602–608

    Google Scholar 

  • Waeber C, Died MM, Hoyer D, Probst A, Palacios JM (1988 a) Visualization of a novel serotonin recognition site (5-HT1D) in the human brain by autoradiography. Neurosci Lett 88:11–16

    Google Scholar 

  • Waeber C, Schoeffter P, Palacios JM, Hoyer D (1988 b) Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes. Naunyn-Schmiedeberg's Arch Pharmacol 337:595–601

    Google Scholar 

Download references

Author information

Affiliations

  1. Preclinical Research, Sandoz Ltd, Building 386/521, CH-4002, Basel, Switzerland

    Philippe Schoeffter & Daniel Hoyer

Authors
  1. Philippe Schoeffter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Hoyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Send offprint requests to D. Hoyer at the above address

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schoeffter, P., Hoyer, D. How selective is GR 43175? Interactions with functional 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors. Naunyn-Schmiedeberg's Arch Pharmacol 340, 135–138 (1989). https://doi.org/10.1007/BF00169219

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00169219

Key words

  • GR 43175
  • 5-HT1 receptor subtypes
  • Adenylate cyclase
  • Inositol phosphates