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.