ADX71441, a novel, potent and selective positive allosteric modulator of the GABA(B) receptor, shows efficacy in rodent models of overactive bladder

作者：Kalinichev M^*; Palea S; Haddouk H; Royer Urios I; Guilloteau V; Lluel P; Schneider M; Saporito M; Poli S

来源：British Journal of Pharmacology, 2014, 171(4): 995-1006.

DOI：10.1111/bph.12517

• allosteric modulation
• GABA(B)
• urinary bladder
• micturition
• overactive bladder
• baclofen
• oxybutynin

Background and PurposeThe GABA(B) receptor agonist baclofen reduces urethral resistance and detrusor overactivity in patients with spasticity. However, baclofen's side effects limit its use for the treatment of overactive bladder (OAB). Here, we tested a novel GABA(B) positive allosteric modulator (PAM) ADX71441 in models of OAB in mice and guinea pigs.
Experimental ApproachMice were left untreated or given (p.o.) vehicle (1% CMC), ADX71441 (1, 3, 10mgkg(-1)) or oxybutynin (100mgkg(-1); Experiment 1) or vehicle (1% CMC), baclofen (1, 3, 6mgkg(-1)) or oxybutynin (Experiment 2). Treated mice were then overhydrated with water, challenged with furosemide, before being placed into micturition chambers and monitored for urinary parameters. In anaesthetized guinea pigs, intravesical infusion of acetic acid was used to induce OAB and the effects of ADX71441 (1, 3mgkg(-1)) or baclofen (1mgkg(-1)), administered i.v., on cystometric parameters were monitored.
Key ResultsIn mice, 10mgkg(-1) ADX71441 increased urinary latencies, reduced the number of urinary events and the total and average urinary volumes. In guinea pigs, ADX71441 (1 and 3mgkg(-1)) increased the intercontraction interval (ICI) and bladder capacity (BC), and reduced micturition frequency (MF) compared to vehicle. At 3mgkg(-1) ADX71441 completely inhibited the micturition reflex and induced overflow incontinence in five out of 10 animals. Baclofen slightly increased ICI and BC and reduced MF.
Conclusion and ImplicationsOur findings demonstrate, for the first time, that a GABA(B) PAM has potential as a novel approach for the treatment of OAB.

• 出版日期2014-2