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

N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-nitrophenyl) cyclohexan ecarboxamide (Rec 15/3079) was synthesized with the aim of obtaining a nove l compound with 5-hydroxytryptamine (5-HT)(1A) antagonistic properties and activity in controlling bladder function at the level of the central nervou s system. Rec 15/3079 showed a selective high affinity for the 5-HT1A recep tor (K-i = 0.2 nM). At the human recombinant 5-HT1A receptor, Rec 15/3079 a cted as a competitive, neutral antagonist in that it did not modify basal [ S-35]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 anta gonized 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)-induced hypothermia i n mice (ID50 = 20 mug/kg) and 8-OH-DPAT-induced forepaw treading in rats (I D50 = 36 mug/kg). In vitro Rec 15/3079 was poorly active in antagonizing ca rbachol-induced bladder (pD(2)' = 5.03) and norepinephrine-induced urethral (apparent pK(b) = 6) contractions. However, in anesthetized rats, Rec 15/3 079 (10-100 mug/kg i.v.) blocked iso-volumic bladder contractions with no e ffect on their amplitude. In conscious rats and guinea pigs with bladders f illed with saline, Rec 15/3079 (300-1000 mug/kg i.v.) increased bladder vol ume capacity (BVC) without affecting bladder contractility. In conscious ra ts with bladders filled with dilute acetic acid, Rec 15/3079 (300 mug/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 antidepressan t activity. Rec 15/3079 showed only a slight decrease in the duration of im mobility in the behavioral despair test (antidepressant activity) at 1 mg/k g i.v. No anxiolytic activity was observed at 10 mg/kg i.v. No effect was o bserved in the hot plate test, but Rec 15/3079 increased tail-flick latenci es after 3 to 10 mg/kg i.v. In conclusion, these studies demonstrate that R ec 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.