A. Leonardi, L. Guarneri, E. Poggesi
Dec 1, 2001
Citations
0
Influential Citations
8
Citations
Quality indicators
Journal
Journal of Pharmacology and Experimental Therapeutics
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-HT1A receptor ( K i = 0.2 nM). At the human recombinant 5-HT1A receptor, Rec 15/3079 acted as a competitive, neutral antagonist in that it did not modify basal [35S]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 p K b value of 10.5. Accordingly, Rec 15/3079 (i.v.) potently antagonized 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)-induced hypothermia in mice (ID50 = 20 μg/kg) and 8-OH-DPAT-induced forepaw treading in rats (ID50 = 36 μg/kg). In vitro Rec 15/3079 was poorly active in antagonizing carbachol-induced bladder (p D ′2 = 5.03) and norepinephrine-induced urethral (apparent p K b = 6) contractions. However, in anesthetized rats, Rec 15/3079 (10–100 μg/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 μg/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 μg/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.