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).
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References
Asarch KB, Ransom RW, Shih JC (1985) 5-HT1A and 5-HT1B selectivity of two phenylpiperazine derivatives: evidence for 5HT1B heterogeneity. Life Sci 36:1265–1273
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 335:588–592
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
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 72:248–254
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 242:552–557
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 83:4086–4088
Cortés R, Palacios JM, Pazos A (1984) Visualization of multiple serotonin receptors in the rat brain by autoradiography. Br J Pharmacol 81:202P
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 255:7108–7117
De Vivo M, Maayani S (1985) Inhibition of forskolin-stimulated adenylate cyclase activity by 5-HT receptor agonists. Eur J Pharmacol 119:231–234
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 238:248–253
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: 467–470
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 Pharmacol33:178–186
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 332:1–7
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
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 29:2375–2380
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) 305:140–142
Hamon M, Cossery JM, Spampinato U, Gozlan H (1986) Are there selective ligands for 5-HT1A and 5-HT1B binding sites in brain? TIPS 7:336–338
Herrick-Davis K, Titeler M (1988) Detection and characterization of the serotonin 5-HT1D receptor in rat and human brain. J Neurochem 50:1624–1631
Heuring RE, Peroutka SJ (1987) Characterization of a novel 3H-5-hydroxytryptamine binding site subtype in bovine brain membranes. J Neurosci 7:894–903
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
Hoyer D, Schoeffter P (1988) 5-HT1D receptors inhibit forskolin-stimulated adenylate cyclase activity in calf substantia nigra. Eur J Pharmacol 147:145–147
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):R89
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 118:13–23
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 376:85–96
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 376:97–107
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 85:357–362
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 339:252–258
Kennett GA, Curzon G (1988) Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 94:137–147
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 291:159–163
Markstein R, Hoyer D, Engel G (1986) 5-HT1A-receptors mediate stimulation of adenylate cyclase in rat hippocampas. Naunyn-Schmiedeberg's Arch Pharmacol 333:335–341
Middlemiss DN, Fozard JR (1983) 8-Hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur J Pharmacol 90:151–153
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 336:245–250
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 136:1–9
Pazos A, Palacios JM (1985) Quantitative auto-radiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230
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 106:539–546
Pazos A, Probst A, Palacios JM (1987) Serotonin receptors in the human brain. III. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 1:97–122
Pedigo NW, Yamamura HI, Nelson DL (1981) Dicrimination of multiple [3H]5-hydroxytryptamine-binding sites by the neuroleptic spiperone in rat brain. J Neurochem 36:220–226
Peroutka SJ (1986) Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B and 5-HT1C binding sites in rat frontal cortex. J Neurochem 47:529–540
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiperidol. Mol Pharmacol 16:687–699
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 139:247–250
Salomon Y, Londos C, Rodbell M (1974) A highly sensitive adenylate cyclase assay. Anal Biochem 58:541–548
Schnellmann RG, Waters SJ, Nelson DL (1984) [3H]5-hydroxytryptamine binding sites: species and tissue variation. J Neurochem 42:65–70
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
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
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 109:427–429
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 31:357–367
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 Pharmacol26:10–18
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 231:480–487
Sprouse JS, Aghajanian GK (1987) Electro-physiological responses of serotonergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse 1:3–9
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 36:3265–3271
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 88:11–16
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 337:595–601
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 337:609–616
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Schoeffter, P., Hoyer, D. Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist?. Naunyn-Schmiedeberg's Arch Pharmacol 339, 675–683 (1989). https://doi.org/10.1007/BF00168661
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DOI: https://doi.org/10.1007/BF00168661