Pharmacological evaluation of JO 1870: relation to the potential treatment of urinary bladder incontinence.
The effect of p.o. administered JO 1870 [(-)-1-(p-chlorophenyl)-N,N- dimethyl-1-ethyl(4-phenyl)-but-3-en-1-ylamine, hydrochloride] on the urinary bladder cystometrogram has been investigated in the unanesthetized rat. The effects of JO 1870 have been compared with those of morphine and reference drugs currently used for the treatment of urinary incontinence in humans. JO 1870 (2.5-25 mg/kg) dose-dependently increased the bladder capacity and the threshold pressure responsible for urination. These effects were antagonized by the i.v. administration of naloxone (0.2 mg/kg). In comparison, morphine (2.5-25 mg/kg) moderately increased urinary volume and threshold pressure. Different anticholinergic drugs (propantheline bromide, 10 mg/kg; terodiline, 25 mg/kg; dicyclomine, 25 mg/kg) had no significant effects on either parameter and the antidepressant clomipramine (25 mg/kg) decreased both. In vitro, JO 1870 specifically displaced [3H]-[D-Ala2,MePhe4,Gly5-(ol)]enkephalin from binding sites in guinea pig whole-brain membranes and rat thalamus; the sodium shift ratio obtained from [3H]naloxone binding was 16. These results suggest that JO 1870 has some opioid agonist activity. JO 1870 (2.5-300 mg/kg) had few effects on cardiorespiratory, gastrointestinal or nociceptive systems in rats. Together, these results indicate that JO 1870 is a nonanticholinergic agent that potently increases bladder capacity, likely through an opioid mechanism, and may have potential use in the treatment of urinary incontinence.
Soulard
C
C
Institut de Recherche Jouveinal, Fresnes, France.
Pascaud
X
X
Roman
F J
FJ
Grouhel
A
A
Junien
J L
JL
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002082:Butylamines / Q000494:pharmacology*; D004123:Dimethylamines / Q000494:pharmacology*; D004745:Enkephalins / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010100:Oxygen / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy*
D002082:Butylamines; D004123:Dimethylamines; D004745:Enkephalins; D011957:Receptors, Opioid; C073384:1-(4-chlorophenyl)-N,N-dimethyl-1-ethyl-(4-phenyl)but-3-en-1-ylamine; D008139:Loperamide; D009020:Morphine; D010100:Oxygen