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Pharmacology and Metabolism of Renzapride

A Novel Therapeutic Agent for the Potential Treatment of Irritable Bowel Syndrome

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Abstract

Background and objective: Renzapride (ATL-1251), a novel benzamide, is currently under clinical development for the treatment of irritable bowel syndrome (IBS). Previous in vitro and in vivo experimental studies have characterized renzapride as a full serotonin 5-HT4 receptor agonist on the gut and a 5-HT3 receptor antagonist. Clinical studies have confirmed the therapeutic efficacy, tolerability and safety of renzapride in patients with constipation-predominant IBS. This study set out to characterize the pharmacological profile of renzapride and its potential metabolic products at both 5-HT and other monoamine receptors in the gut.

Methods: The affinity of renzapride, its (+) and (−) enantiomers, and its primary metabolite, renzapride N-oxide and its enantiomers, for serotonin receptors was assessed by means of in vitro radioligand binding inhibition studies. After membranes prepared from animal tissue or membranes of cell lines transfected with cloned human receptors had been incubated with radiolabelled ligand with high affinity for a specific receptor, renzapride was added to competitively inhibit this binding. Levels of bound radioligand were measured by filtration and counting of the bound radioactivity. In instances where >50% inhibition of radioligand binding had occurred, the inhibition constant (Ki) was calculated. Metabolism of renzapride by liver microsomes was assessed by incubating 10 μmol/L renzapride with human liver microsome samples for 60 minutes at 37°C. After the reaction was stopped, the samples were centrifuged and the supernatant analysed for metabolites by high-pressure liquid chromatography (HPLC). The potential inhibitory effects of renzapride on cytochrome P450 (CYP) enzymes were assessed by incubating renzapride at various concentrations over a 1–500 μmol/L concentration range with microsomes genetically engineered to express a single CYP.

Results: Renzapride was selective for serotonergic receptors and, in particular, had high affinity for human 5-HT3 and guinea-pig 5-HT4 receptors (Ki 17 and 477 nm, respectively). Inhibitory properties at 5-HT2B receptors were also identified for renzapride, as well as some affinity for 5-HT2A and 5-HT2C receptors. Renzapride N-oxide and its enantiomers demonstrated much lower affinity for all 5-HT receptors compared with renzapride. Renzapride was metabolized by liver microsomes to a limited extent and there was no significant non-microsomal metabolism of renzapride. Renzapride did not inhibit the major CYP drug-metabolizing enzymes CYP2C9, CYP2D6, CYP1A2, CYP2A6, CYP2C19, CYP2E1 or CYP3A4 at concentrations consistent with use in a clinical setting.

Conclusions: These results confirm and extend earlier studies in animal and human receptors that show renzapride is a potent and generally full 5-HT4 receptor agonist and 5-HT3 receptor antagonist. The results reported in the present study indicate that the metabolites of renzapride are minor and are unlikely to contribute to its therapeutic profile or lead to interaction of renzapride with other drugs that inhibit the major drug-metabolizing enzymes in the liver at therapeutic doses. These data contribute to the understanding of the pharmacological actions and metabolic fate of renzapride in vivo.

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References

  1. Crowell MD. Role of serotonin in the pathophysiology of the irritable bowel syndrome. Br J Pharmacol 2004; 141: 1285–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol 2004; 2: 895–904

    Article  CAS  PubMed  Google Scholar 

  3. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2006; 23: 1655–65

    Article  CAS  PubMed  Google Scholar 

  4. George A, Meyers NL, Palmer RMJ. Efficacy and safety of renzapride in constipation-predominant IBS: a phase IIB study in the UK primary healthcare setting. Gut 2003; 52: SVI, A91

  5. Sanger GJ, King FD. From metoclopramide to selective gut motility stimulants and 5-HT3 receptor antagonists. Drug Des Deliv 1988; 3: 273–95

    CAS  PubMed  Google Scholar 

  6. Scott LJ, Perry CM. Tegaserod. Drugs 1999; 58: 491–6

    Article  CAS  PubMed  Google Scholar 

  7. Balfour JA, Goa KL, Perry CM. Alosetron. Drugs 2000; 59: 511–8

    Article  CAS  PubMed  Google Scholar 

  8. Buchheit KH, Buhl T. Prokinetic benzamides stimulate peristaltic activity in the isolated guinea pig ileum by activation of 5-HT4 receptors. Eur J Pharmacol 1991; 205: 203–8

    Article  CAS  PubMed  Google Scholar 

  9. Dumuis A, Sebben M, Bockaert J. The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedebergs Arch Pharmacol 1989; 340: 403–10

    Article  CAS  PubMed  Google Scholar 

  10. Elswood CJ, Bunce KT, Humphrey PP. Identification of putative 5-HT4 receptors in guinea-pig ascending colon. Eur J Pharmacol 1991; 196: 149–55

    Article  CAS  PubMed  Google Scholar 

  11. Reeves JJ, Bunce KT, Humphrey PPA. Investigation into the 5-hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus. Br J Pharmacol 1991; 103: 1067–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sanger GJ. Increased gut cholinergic activity and antagonism of 5-hydroxytryptamine M-receptors by BRL 24924: potential clinical importance of BRL 24924. Br J Pharmacol 1987; 91: 77–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wardle KA, Sanger GJ. The guinea-pig distal colon: a sensitive preparation for the investigation of 5-HT4 receptor-mediated contractions. Br J Pharmacol 1993; 110: 1593–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yoshida N, Omoya H, Kato S, et al. 5-HT3 receptor antagonist effects of DAT-582, (R) enantiomer of AS-5370. Eur J Pharmacol 1992; 216: 435–40

    Article  CAS  PubMed  Google Scholar 

  15. Schiavone A, Volonte M, Micheletti R. The gastrointestinal motor effect of benzamide derivatives is unrelated to 5-HT3 receptor blockade. Eur J Pharmacol 1990; 187: 323–9

    Article  CAS  PubMed  Google Scholar 

  16. Song CW, Lee KY, Kim CD, et al. Effect of cisapride and renzapride on gastrointestinal motility and plasma motilin concentration in dogs. J Pharmacol Exp Ther 1997; 281: 312–6

    Google Scholar 

  17. Nagakura Y, Kamato T, Nishida A, et al. Characterization of 5-hydroxytryptamine (5-HT) receptor subtypes influencing colonic motility in conscious dogs. Naunyn Schmiedebergs Arch Pharmacol 1996; 353: 489–98

    Article  CAS  PubMed  Google Scholar 

  18. Cooper SM, McClelland CM, McRichie B, et al. BRL 24924: a new and potent gastric motility stimulant [abstract]. Br J Pharmacol 1986; 88: 383P

    Google Scholar 

  19. Bermudez J, Dunbar A, Sanger GJ, et al. Stimulation of canine gastric motility by BRL 24924, a new gastric prokinetic agent. J Gastrointest Motil 1990; 2: 281–6

    Article  Google Scholar 

  20. Dunbar AW, McClelland CM, Sanger GJ. BRL 24924: a stimulant of gut motility which is also a potent antagonist of the Bezold-Jarisch reflex in anaesthetised rats. Br J Pharmacol 1986; 88: 319P

    Google Scholar 

  21. Gullikson GW, Loeffler RF, Virina MA. Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs. J Pharmacol Exp Ther 1991; 258: 103–10

    CAS  PubMed  Google Scholar 

  22. Meyers NL, Palmer RMJ, Wray HA, et al. Effects of single oral doses of renzapride on gastrointestinal motility in fasted healthy subjects [abstract]. Gut 2002; 51: SIII, A137

  23. Staniforth DH, Pennick M. Human pharmacology of renzapride: a new gastrokinetic benzamide without dopamine antagonist properties. Eur J Clin Pharmacol 1990; 38: 161–4

    Article  CAS  PubMed  Google Scholar 

  24. Briejer MR, Akkermans LM, Schuurkes JA. Gastrointestinal prokinetic benzamides: the pharmacology underlying stimulation of motility. Pharmacol Rev 1995; 47: 631–51

    CAS  PubMed  Google Scholar 

  25. Bach T, Syversveen T, Kvingedal AM, et al. 5-HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle. Naunyn Schmiedebergs Arch Pharmacol 2001; 363: 146–60

    Article  CAS  PubMed  Google Scholar 

  26. Blondel O, Vandecasteele G, Gastineau M, et al. Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium. FEBS Lett 1997; 412: 465–74

    Article  CAS  PubMed  Google Scholar 

  27. Blondel O, Gastineau M, Dahmoune Y, et al. Cloning, expression, and pharmacology of four human 5-hydroxytryptamine type 4 receptor isoforms produced by alternative splicing in the carboxyl terminus. J Neurochem 1998; 70: 2252–61

    Article  CAS  PubMed  Google Scholar 

  28. Claeysen S, Faye P, Sebben M, et al. 5-HT4 receptors: cloning and expression of new splice variants. Ann NY Acad Sci 1997; 861: 49–56

    Article  Google Scholar 

  29. Mialet J, Berque-Bestel I, Eftekhari P, et al. Isolation of the serotoninergic 5-HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6-glial and CHO cell lines. Br J Pharmacol 2000; 129: 771–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mialet J, Berque-Bestel I, Sicsic S, et al. Pharmacological characterization of the human 5-HT4(d) receptor splice variant stably expressed in Chinese hamster ovary cells. Br J Pharmacol 2000; 131: 827–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nagakura Y, Akuzawa S, Miyata K, et al. Pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-HT4 receptor versus human 5-HT3 receptor. Pharmacol Res 1999; 39: 375–82

    Article  CAS  PubMed  Google Scholar 

  32. Pindon A, van Hecke G, van Gompel P, et al. Differences in signal transduction of two 5-HT4 receptor splice variants: compound specificity and dual coupling with Galphas- and Galphai/o-proteins. Mol Pharmacol 2002; 61: 85–96

    Article  CAS  PubMed  Google Scholar 

  33. Steward LJ, Boess FG, Steele JA, et al. Importance of phenylalanine 107 in agonist recognition by the 5-hydroxytryptamine (3A) receptor. Mol Pharmacol 2000; 57: 1249–55

    CAS  PubMed  Google Scholar 

  34. Bockert J, Claeysen S, Compan V, et al. 5-HT4 receptors. Curr Drug Targets — CNS & Neurolog Dis 2004; 3: 39–51

    Article  Google Scholar 

  35. Brattelid T, Kvingedal AM, Krobert KA, et al. Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT4 receptor splice variant, 5-HT4(i). Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 616–28

    Article  CAS  PubMed  Google Scholar 

  36. King FD, Hadley MS, Joiner KT, et al. Substituted benzamides with conformationally restricted side chains: 5. Azabicyclo[x.y.z] derivatives as 5-HT4 receptor agonists and gastric motility stimulants. J Med Chem 1993; 36: 683–9

    Article  CAS  PubMed  Google Scholar 

  37. Martin GR, Humphrey PP. Receptors for 5-hydroxytryptamine: current perspectives on classification and nomenclature. Neuropharmacology 1994; 33: 261–73

    Article  CAS  PubMed  Google Scholar 

  38. Saucier C, Albert PR. Identification of an endogenous 5-hydroxytryptamine type 2A receptor in NIH-3T3 cells: agonist-induced down-regulation involves decreases in receptor RNA and number. J Neurochem 1997; 68: 1998–2011

    Article  CAS  PubMed  Google Scholar 

  39. Bonhaus DW, Bach C, DeSouza A, et al. The pharmacology and distribution of human 5-hydroxytryptamine type 2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol 1995; 115: 622–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wolf WA, Schutz LJ. The serotonin 5-HT2C receptor is a prominent serotonin receptor in basal ganglia: evidence from functional studies on serotonin-mediated phosphoinositide hydrolysis. J Neurochem 1997; 69: 1449–58

    Article  CAS  PubMed  Google Scholar 

  41. Miller K, Weisberg E, Fletcher PW, et al. Membrane-bound and solubilized brain 5HT3 receptors: improved radioligand binding assays using bovine area postrema or rat cortex and the radioligands [3H]-GR65630, [3H]-BRL43694, and [3H]-LY278584. Synapse 1992; 11: 58–66

    Article  CAS  PubMed  Google Scholar 

  42. Boess FG, Steward LJ, Steele JA, et al. Analysis of the ligand binding site of the 5-HT3 receptor using site directed mutagenesis: importance of glutamate 106. Neuropharmacology 1997; 36: 637–47

    Article  CAS  PubMed  Google Scholar 

  43. Grossman CJ, Kilpatrick GJ, Bunce KT. Development of a radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain. Br J Pharmacol 1993; 109: 618–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rees S, den Daas I, Foord S, et al. Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett 1994; 355: 242–6

    Article  CAS  PubMed  Google Scholar 

  45. Monsma Jr FJ, Shen Y, Ward RP, et al. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol 1993; 43: 320–7

    CAS  PubMed  Google Scholar 

  46. Gu H, Wall SC, Rudnick G. Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence. J Biol Chem 1994; 269: 7124–30

    CAS  PubMed  Google Scholar 

  47. Greengrass P, Bremner R. Binding characteristics of [3H]-prazosin to rat brain alpha-adrenergic receptors. Eur J Pharmacol 1979; 55: 323–6

    Article  CAS  PubMed  Google Scholar 

  48. Boyajian CL, Leslie FM. Pharmacological evidence for alpha-2 adrenoceptor heterogeneity: differential binding properties of [3H]-rauwolscine and [3H]-idazoxan in rat brain. J Pharmacol Exp Ther 1987; 241: 1092–8

    CAS  PubMed  Google Scholar 

  49. Broadhurst AM, Alexander BS, Wood MD. Heterogeneous [3H]-rauwolscine binding sites in rat cortex: two alpha 2-adrenoceptor subtypes or an additional non-adrenergic interaction? Life Sci 1988; 43: 83–92

    Article  CAS  PubMed  Google Scholar 

  50. U’Prichard DC, Bylund DB, Snyder SH. (+/−)-[3H]-Epinephrine and (−)[3H]-dihydroalprenolol binding to beta 1- and beta 2-noradrenergic receptors in brain, heart, and lung membranes. J Biol Chem 1978; 253: 5090–102

    PubMed  Google Scholar 

  51. Galli A, DeFelice LJ, Duke BJ, et al. Sodium-dependent norepinephrine-induced currents in norepinephrine-transporter-transfected HEK-293 cells blocked by cocaine and antidepressants. J Exp Biol 1995; 198: 2197–212

    CAS  PubMed  Google Scholar 

  52. Dearry A, Gingrich JA, Falardeau P, et al. Molecular cloning and expression of the gene for a human D1 dopamine receptor. Nature 1990; 347: 72–6

    Article  CAS  PubMed  Google Scholar 

  53. Sunahara RK, Niznik HB, Weiner DM, et al. Human dopamine D1 receptor encoded by an intronless gene on chromosome 5. Nature 1990; 347: 80–3

    Article  CAS  PubMed  Google Scholar 

  54. Zhou QY, Grandy DK, Thambi L, et al. Cloning and expression of human and rat D1 dopamine receptors. Nature 1990; 347: 76–80

    Article  CAS  PubMed  Google Scholar 

  55. Bunzow JR, Van Tol HH, Grandy DK, et al. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 1988; 336: 783–7

    Article  CAS  PubMed  Google Scholar 

  56. Grandy DK, Marchionni MA, Makam H, et al. Cloning of the cDNA and gene for a human D2 dopamine receptor. Proc Natl Acad Sci U S A 1989; 86: 9762–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hayes G, Biden TJ, Selbie LA, et al. Structural subtypes of the dopamine D2 receptor are functionally distinct: expression of the cloned D2A and D2B subtypes in a heterologous cell line. Mol Endocrinol 1992; 6: 920–6

    CAS  PubMed  Google Scholar 

  58. Sokoloff P, Giros B, Martres MP, et al. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 1990; 347: 146–51

    Article  CAS  PubMed  Google Scholar 

  59. Van Tol HH, Wu CM, Guan HC, et al. Multiple dopamine D4 receptor variants in the human population. Nature 1992; 358: 149–52

    Article  PubMed  Google Scholar 

  60. Van Tol HH, Bunzow JR, Guan HC, et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 1991; 350: 610–4

    Article  PubMed  Google Scholar 

  61. Sibley DR, Monsma Jr FJ. Molecular biology of dopamine receptors. Trends Pharmacol Sci 1992; 13: 61–9

    Article  CAS  PubMed  Google Scholar 

  62. Sunahara RK, Guan HC, O’Dowd BF, et al. Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature 1991; 350: 614–9

    Article  CAS  PubMed  Google Scholar 

  63. Weinshank RL, Adham N, Macchi M, et al. Molecular cloning and characterization of a high affinity dopamine receptor (D1 beta) and its pseudogene. J Biol Chem 1991; 266: 22427–35

    CAS  PubMed  Google Scholar 

  64. Giros B, Caron MG. Molecular characterization of the dopamine transporter. Trends Pharmacol Sci 1993; 14: 43–9

    Article  CAS  PubMed  Google Scholar 

  65. Cheng Y, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 1973; 22: 3099–108

    Article  CAS  PubMed  Google Scholar 

  66. Cohen ML, Fludzinski LA. Contractile serotonergic receptor in rat stomach fundus. J Pharmacol Exp Ther 1987; 243: 264–9

    CAS  PubMed  Google Scholar 

  67. Schiavi GB, Brunet S, Rizzi CA, et al. Identification of serotonin 5-HT4 recognition sites in the porcine caudate nucleus by radioligand binding. Neuropharmacology 1994; 33: 543–9

    Article  CAS  PubMed  Google Scholar 

  68. Bender E, Pindon A, van Oers I, et al. Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant. J Neurochem 2000; 74: 478–89

    Article  CAS  PubMed  Google Scholar 

  69. Yoshida N, Mizumoto A, Iwanaga Y, et al. Effects of 5-hydroxytryptamine type 3 receptor antagonists on gastrointestinal motor activity in conscious dogs. J Pharmacol Exp Ther 1991; 256: 272–8

    CAS  PubMed  Google Scholar 

  70. Burke TA, Sanger GJ. Regionally selective cholinergic stimulation by BRL 24924 in the human isolated gut. Br J Clin Pharmacol 1988; 26: 261–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Leclere PG, Lefebvre RA. Presynaptic modulation of cholinergic neurotransmission in the human proximal stomach. Br J Pharmacol 2002; 135: 135–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tam FS, Hillier K, Bunce KT. Characterization of the 5-hydroxy-tryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle. Br J Pharmacol 1994; 113: 143–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Prins NH, Akkermans LM, Lefebvre RA, et al. 5-HT(4) receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle. Br J Pharmacol 2000; 131: 927–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Prins NH, Shankley NP, Welsh NJ, et al. An improved in vitro bioassay for the study of 5-HT4 receptors in the human isolated large intestinal circular muscle. Br J Pharmacol 2000; 129: 1601–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Borman RA, Burleigh DE. Evidence for the involvement of a 5-HT4 receptor in the secretory response of human small intestine to 5-HT. Br J Pharmacol 1993; 110: 927–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Borman RA, Burleigh DE. Heterogeneity of 5-HT receptors mediating secretion in the human intestine. Ann NY Acad Sci 1996; 812: 224–5

    Article  Google Scholar 

  77. Budhoo MR, Harris RP, Kellum JM. The role of the 5-HT4 receptor in Cl-secretion in human jejunal mucosa. Eur J Pharmacol 1996; 314: 109–14

    Article  CAS  PubMed  Google Scholar 

  78. van Wijngaarden I, Tulp MT, Soudijn W. The concept of selectivity in 5-HT receptor research. Eur J Pharmacol 1990; 188: 301–12

    Article  PubMed  Google Scholar 

  79. Spiller RC. Effects of serotonin on intestinal secretion and motility. Curr Opin Gastroenterology 2001; 17: 99–103

    Article  CAS  Google Scholar 

  80. Berman SM, Chang L, Suyenobu B, et al. Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist alosetron. Gastroenterology 2002; 123: 969–77

    Article  CAS  PubMed  Google Scholar 

  81. Friedel D. Ischemic colitis during treatment with alosetron. Gastroenterology 2001; 120: 557–60

    Article  CAS  PubMed  Google Scholar 

  82. Prins NH, Briejer MR, Schuurkes JA. Characterization of the contraction to 5-HT in the canine colon longitudinal muscle. Br J Pharmacol 1997; 120: 714–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Beattie DT, Smith JA, Marquess D, et al. The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol 2004; 143: 549–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Borman RA, Tilford NS, Harmer DW, et al. 5-HT2B receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro. Br J Pharmacol 2002; 135: 1144–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cheng CH, Costall B, Naylor RJ, et al. The effect of 5-HT receptor ligands on the uptake of [3H]5-hydroxytryptamine into rat cortical synaptosomes. Eur J Pharmacol 1993; 239: 211–4

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The research work described in this article was funded entirely by Alizyme Therapeutics Ltd. The radioligand binding and organ bath experiments reported in this study were conducted on behalf of Alizyme in the laboratories of MDS Pharma Services, Taiwan Ltd, Taipei, Taiwan. The human liver microsome studies were conducted on behalf of Alizyme by BioDynamics Research Ltd, Northamptonshire, UK. The authors are both current employees and shareholders of Alizyme Therapeutics Ltd.

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    Nicholas L. Meyers & Roger I. Hickling

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Meyers, N.L., Hickling, R.I. Pharmacology and Metabolism of Renzapride. Drugs R D 9, 37–63 (2008). https://doi.org/10.2165/00126839-200809010-00004

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