Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 339, Issue 6, pp 675–683

Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist?

  • Philippe Schoeffter
  • Daniel Hoyer
Article

Summary

The effects of several putative 5-HT1 receptorsubtype selective ligands were investigated in biochemical 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 phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(mtrifluoromethylphenyl)piperazine), mCPP (1-m-chlorophe-nyl)piperazine, 1 CGS 12066 (7-trifluoromethyl-4-(4-methyl1-piperazinyl)-pyrrolo[1,2-a]quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine). Among reported 5-HT1B receptor selective drugs, TFMPP had similar potency at 5HT1A, 5-HT1B and 5-HT1C receptors, mCPP did not separate between 5-HT1B and 5-HT1C receptors, CGS 12066 was equipotent at 5-HT1B and 5-HT1D receptors, and isamoltane was only slightly 5-HTIB versus 5-HT1A selective. Quipazine showed equal potency at 5-HTIB and 5-HT1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT1A receptor selective, was equally potent at 5-HT1A and 5-HT1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT1 receptor subtype. Of interest were the properties of several of these drugs, which behaved as agonists at some receptors and as antagonists at others (e. g. quipazine, 1-NP, PAPP and isamoltane).

Key words

5-Hydroxytryptamine 5-HT1A 5-HT1B 5-HT1C 5-HT1D receptors Piperazines Adenylate cyclase Inositol phosphates 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Asarch KB, Ransom RW, Shih JC (1985) 5-HT1A and 5-HT1B selectivity of two phenylpiperazine derivatives: evidence for 5HT1B heterogeneity. Life Sci 36:1265–1273Google Scholar
  2. Bockaert J, Dumuis A, Bouhelal R, Sebben M, Cory RN (1987) Piperazine derivatives including the putative anxiolytic drugs, buspirone and ipsapirone, are agonists at 5-HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons. Naunyn-Schmiedeberg's Arch Pharmacol 335:588–592Google Scholar
  3. Bouhelal R, Smounya L, Bockaert J (1988) 5-HT1B receptors are negatively coupled with adenylate cyclase in rat substantia nigra. Eur J Pharmacol 151:189–196Google Scholar
  4. Bradford MM (1976) A rapid and sensitive method for the quantitation of micrograms quantities of protein utilizing the principle of protein-dye-binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  5. Conn PJ, Sanders-Bush E (1987) Relative effcacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT2 and 5-HT1C) receptors. J Pharmacol Exp Ther 242:552–557Google Scholar
  6. Conn PJ, Sanders-Bush E, Hoffman BJ, Hartig PR (1986) A unique serotonin receptor in choroid plexus is linked to phosphatidylinositol turnover. Proc Natl Acad Sci USA 83:4086–4088Google Scholar
  7. Cortés R, Palacios JM, Pazos A (1984) Visualization of multiple serotonin receptors in the rat brain by autoradiography. Br J Pharmacol 81:202PGoogle Scholar
  8. De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J Biol Chem 255:7108–7117Google Scholar
  9. De Vivo M, Maayani S (1985) Inhibition of forskolin-stimulated adenylate cyclase activity by 5-HT receptor agonists. Eur J Pharmacol 119:231–234Google Scholar
  10. De Vivo M, Maayani S (1986) Characterization of 5-hydroxytryptamine1A-receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea-pig and rat hippocampal membranes. J Pharmacol Exp Ther 238:248–253Google Scholar
  11. Dompert WU, Glaser T, Traber J (1985) 3H-TVX Q 7821: Identification of 5-HT1 binding sites as target for a novel putative anxiolytic. Naunyn-Schmiedeberg's Arch Pharmacol 328: 467–470Google Scholar
  12. Dumuis A, Sebben M, Bockaert J (1988) Pharmacology of 5-hydroxytryptamine-1A receptors which inhibit cAMP production in hippocampal and cortical neurons in primary culture. Mol Pharmacol33:178–186Google Scholar
  13. Engel G, Göthert M, Hoyer D, Schlicker E, Hillenbrand K (1986) Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites. Naunyn-Schmiedeberg's Arch Pharmacol 332:1–7Google Scholar
  14. 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 283–335Google Scholar
  15. Glennon RA, Slusher RM, Lyon RA, Titeler M, McKenney JD (1986) 5-HT1 and 5-HT2 binding characteristics of some quipazine analogues. J Med Chem 29:2375–2380Google Scholar
  16. Gozlan H, El Mestikawy S, Pichat L, Glowinski J, Hamon M (1983) Identification of presynaptic serotonin autoreceptors by a new ligand: 3H-PAT. Nature (Lond) 305:140–142Google Scholar
  17. Hamon M, Cossery JM, Spampinato U, Gozlan H (1986) Are there selective ligands for 5-HT1A and 5-HT1B binding sites in brain? TIPS 7:336–338Google Scholar
  18. Herrick-Davis K, Titeler M (1988) Detection and characterization of the serotonin 5-HT1D receptor in rat and human brain. J Neurochem 50:1624–1631Google Scholar
  19. Heuring RE, Peroutka SJ (1987) Characterization of a novel 3H-5-hydroxytryptamine binding site subtype in bovine brain membranes. J Neurosci 7:894–903Google Scholar
  20. 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 72–99Google Scholar
  21. Hoyer D, Schoeffter P (1988) 5-HT1D receptors inhibit forskolin-stimulated adenylate cyclase activity in calf substantia nigra. Eur J Pharmacol 147:145–147Google Scholar
  22. Hoyer D, Dravid A, Palacios JM (1987) Serotonin 5-HT1C receptor mediated hydrolysis of inositol lipids in pig choroid plexus. Naunyn-Schmiedeberg's Arch Pharmacol 335 (Suppl):R89Google Scholar
  23. 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]8OH-DPAT, (−)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin. Fur J Pharmacol 118:13–23Google Scholar
  24. Hoyer D, Pazos A, Probst A, Palacios JM (1986a) 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 376:85–96Google Scholar
  25. Hoyer D, Pazos A, Probst A, Palacios JM (1986b) Serotonin receptors in the human brain II. Characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites. Brain Res 376:97–107CrossRefPubMedGoogle Scholar
  26. Hoyer D, Waeber C, Pazos A, Probst A, Palacios JM (1988) Identification of a 5-HT1 recognition site in human brain membranes different from 5-HT1A, 5-HT1B and 5-HT1C sites. Neurosci Lett 85:357–362Google Scholar
  27. 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 characterization. Naunyn-Schmiedeberg's Arch Pharmacol 339:252–258Google Scholar
  28. Kennett GA, Curzon G (1988) Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 94:137–147Google Scholar
  29. Marcinkiewicz M, Verge D, Gozlan H, Pichat L, Hamon M (1984) Autoradiographic evidence for the heterogeneity of 5-HT1 sites in the rat brain. Brain Res 291:159–163Google Scholar
  30. Markstein R, Hoyer D, Engel G (1986) 5-HT1A-receptors mediate stimulation of adenylate cyclase in rat hippocampas. Naunyn-Schmiedeberg's Arch Pharmacol 333:335–341Google Scholar
  31. Middlemiss DN, Fozard JR (1983) 8-Hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur J Pharmacol 90:151–153Google Scholar
  32. Molderings GJ, Fink K, Schlicker E, Göthert M (1987) Inhibition of noradrenaline release in the rat vena cava via presynaptic 5-HT1B receptors. Naunyn-Schmiedeberg's Arch Pharmacol 336:245–250Google Scholar
  33. Neale RF, Fallon SL, Boyar WC, Wasley JWF, Martin LL, Stone GA, Glaeser BS, Sinton CM, Williams M (1987) Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-IB agonist. Eur J Pharmacol 136:1–9Google Scholar
  34. Pazos A, Palacios JM (1985) Quantitative auto-radiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230Google Scholar
  35. Pazos A, Hoyer D, Palacios M (1984) The binding of serotonergic ligand to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur J Pharmacol 106:539–546Google Scholar
  36. Pazos A, Probst A, Palacios JM (1987) Serotonin receptors in the human brain. III. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 1:97–122Google Scholar
  37. Pedigo NW, Yamamura HI, Nelson DL (1981) Dicrimination of multiple [3H]5-hydroxytryptamine-binding sites by the neuroleptic spiperone in rat brain. J Neurochem 36:220–226Google Scholar
  38. Peroutka SJ (1986) Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B and 5-HT1C binding sites in rat frontal cortex. J Neurochem 47:529–540Google Scholar
  39. Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiperidol. Mol Pharmacol 16:687–699PubMedGoogle Scholar
  40. Ram JL, Kreiman MA, Gole D (1987) LY 165163 and 8-OH-DPAT have agonist effects on a serotonin responsive muscle of Aplysia. Eur J Pharmacol 139:247–250Google Scholar
  41. Salomon Y, Londos C, Rodbell M (1974) A highly sensitive adenylate cyclase assay. Anal Biochem 58:541–548Google Scholar
  42. Schnellmann RG, Waters SJ, Nelson DL (1984) [3H]5-hydroxytryptamine binding sites: species and tissue variation. J Neurochem 42:65–70Google Scholar
  43. 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 95:975–985Google Scholar
  44. 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 337:602–608Google Scholar
  45. Shenker A, Maayani S, Weinstein H, Green JP (1985) Two 5-HT receptors linked to adenylate cyclase in guinea pig hippocampus are discriminated by 5-carboxyamidotryptamine and spiperone. Eur J Pharmacol 109:427–429Google Scholar
  46. Shenker A, Maayani S, Weinstein H, Green JP (1987) Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adylate cyclase in guinea pig hippocampal membranes. Mol Pharmacol 31:357–367Google Scholar
  47. Sills MA, Wolfe BB, Frazer A (1984a) Multiple states of the 5-HT1 receptor as indicated by the effects of GTP on 3H-5-HT binding in rat frontal cortex. Mol Pharmacol26:10–18Google Scholar
  48. Sills MA, Wolfe BB, Frazer A (1984b) Determination of selective and non-selective compounds for the 5-HT1A and 5-HT1B receptor subtypes in the rat frontal cortex. J Pharmacol Exp Ther 231:480–487Google Scholar
  49. Sprouse JS, Aghajanian GK (1987) Electro-physiological responses of serotonergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse 1:3–9Google Scholar
  50. Titeler M, Lyon RA, Herrick-Davis K, Glennon RA (1987) Selectivity of serotonergic drugs for multiple brain serotonin receptors. Role of [3H]-4-bromo-2,5-dimethoxyphenylisopropyl amine ([3H]DOB), a 5-HT2 agonist radioligand. Biochem Pharmacol 36:3265–3271Google Scholar
  51. Waeber C, Died MM, Hoyer D, Probst A, Palacios JM (1988a) Visualization of a novel serotonin recognition site (5-HT1D) in the human brain by autoradiography. Neurosci Lett 88:11–16Google Scholar
  52. Waeber C, Schoeffter P, Palacios JM, Hoyer D (1988b) Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes. NaunynSchmiedeberg's Arch Pharmacol 337:595–601Google Scholar
  53. Waldmeier PC, Williams M, Bauman PA, Bischoff S, Sills MA, Neale RF (1988) Interaction isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivative, with 5-HT1 subtypes in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 337:609–616Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Philippe Schoeffter
    • 1
  • Daniel Hoyer
    • 1
  1. 1.Preclinical ResearchBaselSwitzerland

Personalised recommendations