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Research ArticleDrug Discovery and Translational Medicine

DFL23448, A Novel Transient Receptor Potential Melastin 8–Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

Francesco A. Mistretta, Andrea Russo, Fabio Castiglione, Arianna Bettiga, Giorgia Colciago, Francesco Montorsi, Laura Brandolini, Andrea Aramini, Gianluca Bianchini, Marcello Allegretti, Silvia Bovolenta, Roberto Russo, Fabio Benigni and Petter Hedlund
Journal of Pharmacology and Experimental Therapeutics January 2016, 356 (1) 200-211; DOI: https://doi.org/10.1124/jpet.115.228684
Francesco A. Mistretta
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Andrea Russo
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Fabio Castiglione
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Arianna Bettiga
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Giorgia Colciago
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Francesco Montorsi
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Laura Brandolini
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Andrea Aramini
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Gianluca Bianchini
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Marcello Allegretti
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Silvia Bovolenta
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Roberto Russo
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Fabio Benigni
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Petter Hedlund
Unit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy (F.A.M., A.R., F.C., A.B., G.C., F.M., F.B., P.H.); Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden (F.A.M., P.H.); Università Vita-Salute San Raffaele, Milan, Italy (F.M.); Discovery Department, Research Centre Dompé Farmaceutici SpA, L’Aquila, Italy (L.B., A.A., G.B., M.A.); Discovery Biology, Axxam, Bresso, Milan, Italy (S.B.); Department of Pharmacy, Federico II University of Naples, Naples, Italy (R.R.); and Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Sweden (P.H.)
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Abstract

The transient receptor potential melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity is available. This study characterizes a new TRPM8-selective antagonist (DFL23448 [5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol]) and evaluates it in cold-induced behavioral tests and tests on bladder function and experimental bladder overactivity in vivo in rats. DFL23448 displayed IC50 values of 10 and 21 nM in hTRPM8 human embryonic kidney 293 cells activated by Cooling Agent 10 or cold, but it had limited activity (IC50 > 10 μM) at transient receptor potential vanilloids TRPV1, TRPA1, or TRPV4 or at various G protein–coupled receptors. In rats, DFL23448 administered intravenously or orally had a half-life of 37 minutes or 4.9 hours, respectively. DLF23448 (10 mg/kg i.v.) reduced icilin-induced “wet dog–like” shakes in rats. Intravesical DFL23448 (10 mg/l), but not vehicle, increased micturition intervals, micturition volume, and bladder capacity. During bladder overactivity by intravesical prostaglandin E2 (PGE2), vehicle controls exhibited reductions in micturition intervals, micturition volumes, and bladder capacity by 37%–39%, whereas the same parameters only decreased by 12%–15% (P < 0.05–0.01 versus vehicle) in DFL23448-treated rats. In vehicle-treated rats, but not in DFL23448-treated rats, intravesical PGE2 increased bladder pressures. Intravenous DFL23448 at 10 mg/kg, but not 1 mg/kg DFL23448 or vehicle, increased micturition intervals, micturition volumes, and bladder capacity. During bladder overactivity by intravesical PGE2, micturition intervals, micturition volumes, and bladder capacity decreased in vehicle– and 1 mg/kg DFL23448–treated rats, but not in 10 mg/kg DFL23448–treated rats. Bladder pressures increased less in rats treated with DFL23448 10 mg/kg than in vehicle– or 1 mg/kg DFL23448–treated rats. DFL23448 (10 mg/kg i.v.), but not vehicle, prevented cold stress–induced bladder overactivity. Our results support a role for bladder TRPM8-mediated signals in experimental bladder overactivity.

Footnotes

    • Received August 14, 2015.
    • Accepted November 5, 2015.
  • This research was supported by an unrestricted grant from Dompe Pharmaceuticals and the Gester Foundation.

  • dx.doi.org/10.1124/jpet.115.228684.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 1
1 Jan 2016
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Research ArticleDrug Discovery and Translational Medicine

TRPM8 as a Drug Target in Models for Bladder Overactivity

Francesco A. Mistretta, Andrea Russo, Fabio Castiglione, Arianna Bettiga, Giorgia Colciago, Francesco Montorsi, Laura Brandolini, Andrea Aramini, Gianluca Bianchini, Marcello Allegretti, Silvia Bovolenta, Roberto Russo, Fabio Benigni and Petter Hedlund
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 200-211; DOI: https://doi.org/10.1124/jpet.115.228684

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Research ArticleDrug Discovery and Translational Medicine

TRPM8 as a Drug Target in Models for Bladder Overactivity

Francesco A. Mistretta, Andrea Russo, Fabio Castiglione, Arianna Bettiga, Giorgia Colciago, Francesco Montorsi, Laura Brandolini, Andrea Aramini, Gianluca Bianchini, Marcello Allegretti, Silvia Bovolenta, Roberto Russo, Fabio Benigni and Petter Hedlund
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 200-211; DOI: https://doi.org/10.1124/jpet.115.228684
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