Premium
ADX 71441, a novel, potent and selective positive allosteric modulator of the GABA B receptor, shows efficacy in rodent models of overactive bladder
Author(s) -
Kalinichev M,
Palea S,
Haddouk H,
RoyerUrios I,
Guilloteau V,
Lluel P,
Schneider M,
Saporito M,
Poli S
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12517
Subject(s) - overactive bladder , urination , baclofen , agonist , urinary bladder , chemistry , endocrinology , oxybutynin , urinary system , medicine , pharmacology , receptor , anesthesia , alternative medicine , pathology
Background and Purpose The 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 ) ADX 71441 in models of OAB in mice and guinea pigs. Experimental Approach Mice were left untreated or given (p.o.) vehicle (1% CMC ), ADX 71441 (1, 3, 10 mg kg −1 ) or oxybutynin (100 mg kg −1 ; Experiment 1) or vehicle (1% CMC ), baclofen (1, 3, 6 mg kg −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 ADX 71441 (1, 3 mg kg −1 ) or baclofen (1 mg kg −1 ), administered i.v., on cystometric parameters were monitored. Key Results In mice, 10 mg kg −1 ADX 71441 increased urinary latencies, reduced the number of urinary events and the total and average urinary volumes. In guinea pigs, ADX 71441 (1 and 3 mg kg −1 ) increased the intercontraction interval ( ICI ) and bladder capacity ( BC ), and reduced micturition frequency ( MF ) compared to vehicle. At 3 mg kg −1 ADX 71441 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 Implications Our findings demonstrate, for the first time, that a GABA B PAM has potential as a novel approach for the treatment of OAB .