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

Abstract

BACKGROUND AND PURPOSEThe GABAB 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 GABAB 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, 10 mg kg ) 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, 3 mg kg ), administered i.v., on cystometric parameters were monitored. KEY RESULTSIn mice, 10 mg kg −1 ADX71441 increased urinary latencies, reduced the number of urinary events and the total and average urinary volumes. In guinea pigs, ADX71441 (1 and 3 mg kg ) increased the intercontraction interval (ICI) and bladder capacity (BC), and reduced micturition frequency (MF) compared to vehicle. At 3 mg kg −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 GABAB PAM has potential as a novel approach for the treatment of OAB. AbbreviationsAA, acetic acid; BC, bladder capacity; BP, basal pressure; ICI, intercontraction interval; i.ves, intravesical; MF, micturition frequency; MIA, monosodium iodoacetate; OAB, overactive bladder; ThP, threshold volume BJP British Journal of Pharmacology

Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice

“…Previously, in a series of in vitro and in vivo studies, ADX71441 has been characterized as a potent, selective, reversible, and orally bioavailable GABA B R PAM active in models of pain, anxiety (Kalinichev et al 2013a, under review), and overactive bladder (Kalinichev et al 2013b, under review). Here we tested ADX71441 in mouse models of binge drinking and long-term high-dose drinking.…”

“…In both experiments, opioid antagonist, naltrexone, was used as a positive control for medications already available in the clinic (Volpicelli et al 1992; O’Malley et al 1992; Kranzler and Kirk 2001; Anton et al 2006). We hypothesized that ADX71441 would result in a robust and specific reduction of ethanol intake which is likely to be longer lasting than that of naltrexone, based on the differences in the duration of action between the two compounds (Kamdar et al 2007; Kalinichev et al 2013a, b, under review).…”

The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia

“…Unlike direct agonists of glutamate receptors, most of which act as glutamate analogs and bind directly to the ligand-binding site, mGlur 4 PAMs bind to a distinct allosteric site, allowing more specificity. ADX88178 is a next-generation mGlur 4 PAM which is potent, selective, and orally bioavailable (Kalinichev et al 2014). It is effective in rodent models of parkinsonism (Le Poul et al 2012), and is considered a prototype for compounds that will advance to clinical testing.…”

Activation of the γ-Aminobutyric Acid Type B (GABAB) Receptor by Agonists and Positive Allosteric Modulators

“…81 The identification of new PAMs of the GABA B receptor continues to be an area of substantial interest due to the therapeutic potential, and new molecules are appearing in the literature, such as the PAM ADX71441 (structure not disclosed). 82 Additionally, the arylalkylamines were reported to display activity as PAMs of the GABA B receptor, 83 but subsequent evaluation in GTP(γ) 35 Sbinding assays in the presence of GABA did not support that these molecules act in this fashion on the GABA B receptor. 84 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Negative allosteric modulators (NAMs) for the GABA B receptor were not known until 2014 and the first report described the discovery of a compound designed from CGP7930.…”