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N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-nitrophenyl) cyclohexanecarboxamide: a novel pre- and postsynaptic 5-hydroxytryptamine(1A) receptor antagonist active on the lower urinary tract.

Abstract
N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-nitrophenyl) cyclohexanecarboxamide (Rec 15/3079) was synthesized with the aim of obtaining a novel compound with 5-hydroxytryptamine (5-HT)(1A) antagonistic properties and activity in controlling bladder function at the level of the central nervous system. Rec 15/3079 showed a selective high affinity for the 5-HT(1A) receptor (K(i) = 0.2 nM). At the human recombinant 5-HT(1A) receptor, Rec 15/3079 acted as a competitive, neutral antagonist in that it did not modify basal [(35)S]guanosine-5'-O-(3-thio)triphosphate binding to HeLa cell membranes but shifted the activation isotherm to 5-HT to the right, in a parallel manner, with a pK(b) value of 10.5. Accordingly, Rec 15/3079 (i.v.) potently antagonized 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)-induced hypothermia in mice (ID(50) = 20 microg/kg) and 8-OH-DPAT-induced forepaw treading in rats (ID(50) = 36 microg/kg). In vitro Rec 15/3079 was poorly active in antagonizing carbachol-induced bladder (pD'(2) = 5.03) and norepinephrine-induced urethral (apparent pK(b) = 6) contractions. However, in anesthetized rats, Rec 15/3079 (10-100 microg/kg i.v.) blocked isovolumic bladder contractions with no effect on their amplitude. In conscious rats and guinea pigs with bladders filled with saline, Rec 15/3079 (300-1000 microg/kg i.v.) increased bladder volume capacity (BVC) without affecting bladder contractility. In conscious rats with bladders filled with dilute acetic acid, Rec 15/3079 (300 microg/kg i.v.) reversed the decrease of BVC induced by the acid. To evaluate apparent selective effect on lower urinary tract reflexes, Rec 15/3079 was tested in experimental models for sedative, analgesic, anxiolytic, and antidepressant activity. Rec 15/3079 showed only a slight decrease in the duration of immobility in the behavioral despair test (antidepressant activity) at 1 mg/kg i.v. No anxiolytic activity was observed at 10 mg/kg i.v. No effect was observed in the hot plate test, but Rec 15/3079 increased tail-flick latencies after 3 to 10 mg/kg i.v. In conclusion, these studies demonstrate that Rec 15/3079 is endowed with favorable effects on bladder function, and it is devoid of unwanted side effects at the level of central nervous system at doses at least 10-fold higher than those active on the bladder.
AuthorsA Leonardi, L Guarneri, E Poggesi, P Angelico, C Velasco, A Cilia, R Testa
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 299 Issue 3 Pg. 1027-37 (Dec 2001) ISSN: 0022-3565 [Print] United States
PMID11714892 (Publication Type: Journal Article)
Chemical References
  • Analgesics
  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Piperazines
  • REC 15-3079
  • Receptors, Presynaptic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists
  • Sulfur Radioisotopes
  • Guanosine 5'-O-(3-Thiotriphosphate)
Topics
  • Analgesics (pharmacology)
  • Anesthesia
  • Animals
  • Anti-Anxiety Agents (pharmacology)
  • Antidepressive Agents (pharmacology)
  • Central Nervous System (drug effects, physiology)
  • Female
  • Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
  • Guinea Pigs
  • Infusions, Intravenous
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neurotoxicity Syndromes
  • Piperazines (adverse effects, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Presynaptic (drug effects)
  • Receptors, Serotonin (metabolism)
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists (adverse effects, pharmacology)
  • Sulfur Radioisotopes
  • Urethra (drug effects, metabolism)
  • Urinary Bladder (drug effects, metabolism)
  • Urinary Tract (drug effects, metabolism)
  • Uterine Contraction (drug effects)

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