| Field | Specification |
|---|---|
| CAS no. | |
| Applications | |
| Molecular weight | |
| Molecular formula | C19H15ClF2N4O4 |
| Purity | |
| SMILES | |
| Form | Solid |
| Storage | |
| Shipping | |
| Catalog no. (Mfr.) | |
| Main SKU |
Compound Overview
ADX71441 is an orally active, blood-brain-barrier-penetrant positive allosteric modulator of the GABA B receptor, potentiating the activity of endogenous GABA at this receptor with an EC50 of 96 nM. It also functionally inhibits adenosine transporters and the 5-HT2B receptor. It produces anxiolytic-like, analgesic, muscle-relaxant, hypothermic and overactive-bladder-inhibitory effects, reduces acute locomotor activity, decreases voluntary intake of alcohol and saccharin, attenuates stress-induced neuronal activation, and shows anti-hyperalgesic activity[1][2][3][4]. It is supplied as a white to off-white solid (C19H15ClF2N4O4, MW 436.80) at 98.63% purity.
Physical & Chemical Properties
| CAS Number | 1207440-88-7 |
|---|---|
| Molecular Formula | C19H15ClF2N4O4 |
| Molecular Weight | 436.80 g/mol |
| Purity | 98.63% |
| Appearance | Solid |
| Color | White to off-white |
| SMILES | O=C(N(C1=O)CC2=CC=C(C(F)=C2)Cl)C(OC)=NN1C3=CC=C(C(NC(C)=O)=C3)F |
| Signaling Pathway | Membrane Transporter/Ion Channel; Neuronal Signaling; GPCR/G Protein |
| Storage | Powder: -20°C, 3 years; 4°C, 2 years. In solvent: -80°C, 6 months; -20°C, 1 month. |
| Shipping | Room temperature in continental US; may vary elsewhere. |
Literature Cited
Sources cited in this description and in the In Vitro & In Vivo Data tab. Peer-reviewed publications that used this product are listed under References.
[1]. Kalinichev M, et al. The drug candidate, ADX71441, is a novel, potent and selective positive allosteric modulator of the GABAB receptor with a potential for treatment of anxiety, pain and spasticity. Neuropharmacology. 2017 Mar 1;114:34-47.
Safety
For Research Use Only. Not for use in diagnostic or therapeutic procedures, and not for human or veterinary use. Handle in accordance with the Safety Data Sheet and your institution's chemical hygiene plan.
In Vitro
In HEK293 cells, ADX71441 (10-10 to 10-3 M; 180 s) serves as a positive allosteric modulator of recombinant human GABAB receptors: it potentiates GABA-induced calcium mobilization with an EC50 of 29 ± 9 nM, has no significant direct agonist activity, and binds the receptor reversibly[1]. At endogenous rat cortical GABAB receptors, ADX71441 (10−13 to 10−3 M; 30 min + 30 min) enhances GABA-induced G-protein activation with an EC50 of 53 ± 14 nM, raising both the potency and efficacy of GABA[1]. At endogenous human cortical GABAB receptors, ADX71441 (10-13 to 10-3 M; 30 min + 30 min) enhances GABA-induced G-protein activation with an EC50 of 40 ± 7 nM, significantly raising the potency and efficacy of GABA[1]. ADX71441 (10 μM, up to 30 μM) is very selective for GABAB receptors: no activity is seen on mGlu receptors, and off-target activity is weak, at the 5-HT2B receptor (IC50 6.06 μM) and the adenosine transporter (IC50 0.24 μM)[1].
In Vivo
In the mouse pellet-burying test, ADX71441 (1-10 mg/kg; p.o.; single administration) gives a dose-dependent anxiolytic-like effect, the minimum effective dose being 3 mg/kg[1]. ADX71441 (1-10 mg/kg; p.o.; single administration) elicits dose-dependent anxiolytic-like effects in the elevated plus-maze test in mice, and the minimum effective dose is 3 mg/kg[1]. In rats, ADX71441 (0.3-3 mg/kg; p.o.; single administration) evokes an anxiolytic-like effect in the elevated plus-maze test that is dose-dependent, and the lowest effective dose is 3 mg/kg[1]. Anxiolytic-like effects of ADX71441 (30 mg/kg; p.o.; single administration) in the rat elevated plus-maze test are still detectable 24 hours after administration[1]. In the mouse writhing test induced by acetic acid, ADX71441 (1-10 mg/kg; p.o.; single administration) shows analgesic effects that depend on both dose and time[1]. Muscle relaxation in the rat rotarod test is induced by ADX71441 (10 mg/kg; p.o.; single administration)[1]. In mice given acute intragastric administration, ADX71441 (10 mg/kg; p.o.; single administration) lowers spontaneous locomotor activity[1]. Following acute oral administration, ADX71441 (3-30 mg/kg; p.o.; single dose) lowers spontaneous locomotor activity in rats in a dose-dependent way, and the minimum effective dose is 3 mg/kg[1]. In mice, tolerance to the motor-suppressant effect of ADX71441 develops with subchronic oral administration (30 mg/kg; p.o.; once daily for 7 consecutive days)[1]. Activation of GABAB receptors underlies a dose-dependent hypothermic effect of ADX71441 (3-30 mg/kg; p.o.; single administration) in mice, with 10 mg/kg as the minimum effective dose[1]. ADX71441 (3-30 mg/kg; p.o.; single administration) causes a transient, dose-dependent hypothermic effect in rats, and 3 mg/kg is the minimum effective dose[1]. In a furosemide-induced overactive bladder (OAB) model in mice, ADX71441 (1-10 mg/kg; p.o.; single administration) lowers the total number of micturition episodes, the total urine volume, and the average urine volume in a dose-dependent manner, and lengthens the first micturition latency[2]. ADX71441 (1-3 mg/kg; i.v.; single administration) quickly improves urodynamic parameters in guinea pigs with overactive bladder (OAB) induced by acetic acid[2]. In non-addicted male Wistar rats, ADX71441 (1-30 mg/kg; i.p.; single administration) dose-dependently reduces 20% voluntary alcohol intake[3]. ADX71441 (1-3 mg/kg; i.p.; single administration) shows greater efficacy at lowering alcohol self-administration behavior in male Wistar rats that are alcohol-dependent[3]. In male Wistar rats trained to consume alcohol voluntarily, ADX71441 (3-10 mg/kg; i.p.; single administration) potently blocks alcohol relapse-like drinking behavior induced by cues and by stress[3]. ADX71441 (3 mg/kg; i.p.; single administration) attenuates neuronal activation induced by stress across the network of brain regions (nucleus accumbens shell, central amygdala, the dorsal raphe nucleus, and the medial prefrontal cortex) linked to relapse-like alcohol-seeking behavior induced by stress in male Wistar rats[3]. In a rat osteoarthritis model induced by Sodium iodoacetate, ADX71441 (0.3-15 mg/kg; p.o.; once daily for 7 consecutive days) displays dose-dependent anti-allodynic efficacy[4]. Muscle relaxant effects are exerted in rats by ADX71441 (1-10 mg/kg; p.o.; single administration)[4].
| Animal Model | C57Bl6/J (male, adult, 24-30g)[1] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg |
| Administration | p.o.; single dose; 60 minutes pre-test |
| Result | Showed no effect at 1 mg/kg. Produced a ~55% reduction in buried marbles at 3 mg/kg. Fully suppressed burying behavior at 10 mg/kg. Reached mean plasma concentrations of 144 ng/mL (1 mg/kg), 341 ng/mL (3 mg/kg), and 629 ng/mL (10 mg/kg) at end of experiment.\nShowed no effect at 1 mg/kg. Produced ~2-fold increases in open arm entries at 3 mg/kg and 10 mg/kg. Produced a ~2-fold increase in time spent on open arms at 3 mg/kg, and an almost 3-fold increase at 10 mg/kg. Showed no effect on closed arm exploration. Reached mean plasma concentrations of 168 ng/mL (1 mg/kg), 399 ng/mL (3 mg/kg), and 688 ng/mL (10 mg/kg) at end of experiment. |
| Animal Model | Sprague-Dawley (male, adult, 250-350g)[1] |
|---|---|
| Dosage | 0.3 mg/kg; 1 mg/kg; 3 mg/kg |
| Administration | p.o.; single dose; 60 minutes pre-test |
| Result | Showed no effect at 0.3 mg/kg and 1 mg/kg. Produced more than 3-fold increases in open arm entries and more than 4-fold increases in time spent on open arms at 3 mg/kg. Showed no effect on closed arm exploration. Reached mean plasma concentrations of 46 ng/mL (1 mg/kg), 171 ng/mL (3 mg/kg) at end of experiment. |
| Animal Model | Sprague-Dawley (male, adult, 250-350g)[1] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg; 30 mg/kg |
| Administration | p.o.; single dose; 24 hours pre-test |
| Result | Showed no effect at 1 mg/kg and 3 mg/kg. Showed a trend toward reduced open arm entries at 10 mg/kg. Produced almost 4-fold increases in open arm entries and almost 4-fold increases in time spent on open arms at 30 mg/kg. Showed no effect on closed arm entries. Reached mean brain concentrations of 40 ng/g (1 mg/kg), 107 ng/g (3 mg/kg), 427 ng/g (10 mg/kg), and 1014 ng/g (30 mg/kg); mean plasma concentrations of 11 ng/mL (1 mg/kg), 52 ng/mL (3 mg/kg), 321 ng/mL (10 mg/kg), and 898 ng/mL (30 mg/kg) at end of experiment. |
| Animal Model | C57Bl6/J (male, adult, 24-30g; separate cohort from SLAC, Shanghai, China)[1] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg |
| Administration | p.o.; single dose; 70 minutes pre-test (dose-response); 1, 2, 4 hours pre-test (time-course) |
| Result | Showed no effect at 1 mg/kg in dose-response study. Produced a 55% reduction in writhes at 3 mg/kg, and an almost 90% reduction at 10 mg/kg in dose-response study. Produced an ~80% reduction in writhes at 1 hour post-treatment, ~60% reduction at 2 hours, and ~25% reduction (trend) at 4 hours with 10 mg/kg in time-course study. Reached mean plasma concentrations of 562 ng/mL (1 hour), 566 ng/mL (2 hours), and 343 ng/mL (4 hours) in time-course study. |
| Animal Model | Sprague-Dawley (male, adult, 250-350g)[1] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg |
| Administration | p.o.; single dose; measured at 60, 120, 180 minutes post-treatment |
| Result | Showed no effect at 1 mg/kg and 3 mg/kg across all time points. Reduced time on rotarod by approximately 50% at all time points at 10 mg/kg. |
| Animal Model | C57Bl6/J (male, adult, 24-30g)[1] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg |
| Administration | p.o.; single dose; 60 minutes pre-test; monitored for 60 minutes |
| Result | Showed no effect at 1 mg/kg and 3 mg/kg. Produced a ~40% reduction in total distance travelled at 10 mg/kg. |
| Animal Model | Sprague-Dawley (male, adult, 250-350g)[1] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg; 30 mg/kg |
| Administration | p.o.; single dose; 60 minutes pre-test; monitored for 60 minutes |
| Result | Showed no effect at 1 mg/kg. Produced an ~50% reduction in total distance travelled at 3 mg/kg, ~85% reduction at 10 mg/kg, and almost 100% reduction at 30 mg/kg. |
| Animal Model | C57Bl6/J (male, adult, 24-30g; cohort from Charles River Laboratories, Wilmington, MA)[1] |
|---|---|
| Dosage | 10 mg/kg; 30 mg/kg |
| Administration | p.o.; once daily for 7 days plus acute dose on day 8; 60 minutes pre-test on day 8; monitored for 60 minutes |
| Result | Showed no reduction in locomotor activity (total distance travelled or rearing) with acute 30 mg/kg dose in mice with sub-chronic 30 mg/kg treatment history. Produced an ~50% reduction in total distance travelled and ~90% reduction in rears with acute 30 mg/kg dose, and no effect with acute 10 mg/kg dose in vehicle-treated mice. |
| Animal Model | C57Bl6/J (male, adult, 24-30g; cohort from Janvier, Le Genest Saint Isle, France)[1] |
|---|---|
| Dosage | 3 mg/kg; 10 mg/kg; 30 mg/kg |
| Administration | p.o.; single dose; measured at 1, 2, 4 hours post-treatment (acute); p.o. 30 mg/kg plus oral CGP63360 30 minutes later (target engagement) |
| Result | Showed no effect at 3 mg/kg in acute dose-response study. Produced a 1.5°C reduction at 1 and 2 hours at 10 mg/kg, and a ~3°C reduction at 1 and 2 hours plus 1.77°C reduction at 4 hours at 30 mg/kg in acute dose-response study. Had hypothermic effects dose-dependently reversed by CGP63360 in target engagement study; 3 mg/kg CGP63360 returned body temperature to normal at 2 and 4 hours post-ADX71441 treatment. |
| Animal Model | Sprague-Dawley (male, adult, 250-350g)[1] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg; 30 mg/kg |
| Administration | p.o.; single dose; measured at 1, 2, 4, 20 hours post-treatment |
| Result | Showed no effect at 1 mg/kg. Produced 0.5-1.2°C reductions at 1, 2, and 4 hours at 3 mg/kg and 10 mg/kg. Produced 1.4-1.8°C reductions at 1, 2, and 4 hours at 30 mg/kg. Showed no effect at 20 hours post-treatment across all doses. |
| Animal Model | C57Bl6/J (adult male, 24-30 g, overhydrated with water and challenged with furosemide to induce bladder overactivity)[2] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg |
| Administration | p.o.; single dose |
| Result | Produced a 70% reduction in total urinary events, a more than threefold increase in latency to the first urinary event, a 55% reduction in total urinary volume, and an approximately 65% reduction in average urinary volume compared to vehicle-treated mice at 10 mg/kg. Normalized urinary parameters to levels not significantly different from intact untreated controls for number of urinary events, latency to first event, and average urinary volume at 3 mg/kg and 10 mg/kg. Normalized total urinary volume to levels not significantly different from intact untreated controls at 10 mg/kg. Achieved plasma concentrations of 101 ng/mL (1 mg/kg), 208 ng/mL (3 mg/kg), and 652 ng/mL (10 mg/kg), corresponding to unbound plasma concentration/EC50 ratios of 0.36, 0.74, and 2.31 respectively. |
| Animal Model | Dunkin Hartley (adult female, 290-370 g, OAB induced by intravesical infusion of 0.2% acetic acid)[2] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg |
| Administration | i.v.; single bolus dose |
| Result | Significantly increased intercontraction interval and bladder capacity at 1 mg/kg and 3 mg/kg 0-15 minutes post-administration. Significantly reduced micturition frequency compared to vehicle at 1 mg/kg 0-15 minutes post-administration. Significantly increased threshold pressure compared to vehicle at 3 mg/kg 0-15 minutes post-administration. Completely inhibited the micturition reflex, inducing overflow incontinence, in 5 out of 10 animals at 3 mg/kg. Achieved plasma concentrations of 67 ng/mL (1 mg/kg) and 195 ng/mL (3 mg/kg), corresponding to unbound plasma concentration/EC50 ratios of 0.3 and 0.9 respectively. |
| Animal Model | Wistar rats (adult male, 200-225g at study initiation, trained to self-administer 20% alcohol on FR2 schedule)[3] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg; 30 mg/kg |
| Administration | i.p. |
| Result | Showed no significant reduction in alcohol reinforcers earned or active lever presses, and no effect on locomotor activity at 1 mg/kg. Produced statistically significant reduction in alcohol reinforcers earned and active lever presses, no alteration to locomotor activity, and potent reduction in alcohol breakpoints at 3 mg/kg. Produced statistically significant reduction in alcohol reinforcers earned and active lever presses, no alteration to locomotor activity, and potent reduction in alcohol breakpoints at 10 mg/kg. Produced statistically significant reduction in alcohol reinforcers earned and active lever presses, and significant reduction in locomotor activity at 30 mg/kg. |
| Animal Model | Wistar rats (adult male, 200-225g at study initiation; alcohol-dependent via chronic intermittent 14-hour daily alcohol vapor exposure for 8 weeks; non-dependent control exposed to normal air)[3] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg |
| Administration | i.p. |
| Result | Significantly decreased alcohol reinforcers earned and active lever presses in alcohol-dependent rats but had no significant effect in non-dependent rats at 1 mg/kg. Significantly decreased alcohol reinforcers earned and active lever presses in both alcohol-dependent and non-dependent rats at 3 mg/kg. |
| Animal Model | Wistar rats (adult male, 200-225g at study initiation, trained to self-administer 20% alcohol, extinction trained for alcohol-seeking behavior)[3] |
|---|---|
| Dosage | 3 mg/kg; 10 mg/kg |
| Administration | i.p. |
| Result | Potently blocked cue-induced relapse-like alcohol seeking and stress-induced relapse-like alcohol seeking at 3 mg/kg. Potently blocked cue-induced relapse-like alcohol seeking and stress-induced relapse-like alcohol seeking at 10 mg/kg. |
| Animal Model | Wistar rats (adult male, 200-225g at study initiation, trained to self-administer 20% alcohol, extinction trained for alcohol-seeking behavior)[3] |
|---|---|
| Dosage | 3 mg/kg |
| Administration | i.p. |
| Result | Significantly decreased c-Fos expression in the nucleus accumbens shell, central amygdala, and dorsal raphe nucleus compared to vehicle. Showed a trend for reduced c-Fos expression in the medial prefrontal cortex. Significantly suppressed activation of a stress-responsive brain network consisting of the dorsal raphe nucleus, nucleus accumbens shell, and medial prefrontal cortex, whose activity correlated strongly with stress-induced relapse-like behavior. |
| Animal Model | Sprague-Dawley rats (adult male, 250-350 g, monosodium iodoacetate-induced osteoarthritis)[4] |
|---|---|
| Dosage | 0.3 mg/kg; 1 mg/kg; 3 mg/kg; 15 mg/kg |
| Administration | p.o.; once daily; 7 days |
| Result | Produced a 2-fold increase in ipsilateral joint compression threshold 2 hours post-administration, as well as 1.3-fold and 1.7-fold increases 1 and 4 hours post-administration, respectively, with 15 mg/kg acutely on post-MIA day 14. Showed no significant acute efficacy on day 14 with 0.3, 1, 3 mg/kg. Produced consistent 1.5-fold increases in joint compression threshold at all tested time points with 15 mg/kg on post-MIA day 21 after 7 days of daily treatment. Produced statistically significant, modest increases in joint compression threshold, particularly at 2 and 4 hours post-dosing, with 1 mg/kg and 3 mg/kg on post-MIA day 21 after 7 days of daily treatment. |
| Animal Model | Sprague-Dawley rats (adult male, 250-350 g, rotarod-tested healthy)[4] |
|---|---|
| Dosage | 1 mg/kg; 3 mg/kg; 10 mg/kg |
| Administration | p.o.; single dose |
| Result | Had no significant effect on time spent on the rotarod with 1 mg/kg and 3 mg/kg. Produced an approximately 50% reduction in time spent on the rotarod 2 and 3 hours post-dosing compared with vehicle treatment with 10 mg/kg. |
Data provided by the manufacturer. Numbered citations refer to the Literature Cited list in the product description.
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