Multitargeted Compounds Derived from (2,5-Dioxopyrrolidin-1-yl)(phenyl)-Acetamides as Candidates for Effective Anticonvulsant and Antinociceptive Agents

Abstract

We developed a focused set of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant and antinociceptive properties. These hybrid compounds demonstrated broad-spectrum protective activity in a range of mouse models, such as the maximal electroshock (MES) test, the pentylenetetrazole-induced seizures (scPTZ), and the 6 Hz (32 mA) seizures. Compound 22 showed the most potent anticonvulsant activity (ED50 MES = 23.7 mg/kg, ED50 6 Hz (32 mA) = 22.4 mg/kg, ED50 scPTZ = 59.4 mg/kg). In addition, 22 revealed potent efficacy in the formalin-induced tonic pain. These in vivo activities of 22 are likely mediated by several targets and may result from the inhibition of central sodium/calcium currents and transient receptor potential vanilloid 1 (TRPV1) receptor antagonism. Finally, the lead compound 22 revealed drug-like absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) properties in the in vitro assays, making it a potential candidate for further development in epilepsy and neuropathic pain indications.

KA‐104, a new multitargeted anticonvulsant with potent antinociceptive activity in preclinical models

“…PGB was used as the second reference drug, which together with gabapentin (GBP) is one of the two most often used AEDs in the clinical management on neuropathic pain. 17 Because KA-104 was active in phase 1 of the formalin test, showing the potential to inhibit the neurogenic (acute) response to noxious stimuli, 15 we decided to confirm this property in the capsaicin-induced pain model. Capsaicin activates the transient receptor potential cation channel subfamily V member 1 (TRPV1), which has been implicated in many different kinds of pain, including neuropathic pain.…”

“…In the spontaneous locomotor activity test, KA-104 with the ED 50 value of 22.7 mg/kg in mice revealed similar sedative properties as PGB. 15 The results obtained with KA-104, and other reference compounds tested in neuropathic pain models, should be interpreted with caution, because experimental endpoints in such models rely on behavioral observations, which can be confounded by effects such as somnolence or motor impairment. 36 Although it is difficult to fully translate these behavioral effects from rodents to humans, it is noteworthy that KA-104 induced motor impairment in mice only at doses that were much than those producing analgesic effects and its median behavior-impairing dose value in the rotarod test was equal to 195.7 mg/kg.…”

“…The pharmacokinetic profile of KA-104 was examined after its ip administration in adult male Albino Swiss mice (CD-1, 18-21 g) at the dose of 20 mg/kg (approximately equal to its ED 50 from MES and 6-Hz [32-mA] seizure tests, obtained previously 15 ). The amount of the test compound in plasma and brain was determined by liquid chromatography electrospray ionization tandem mass spectrometric (LC/ESI-MS/ MS) system.…”

“…The strategy of multifunctional anticonvulsants based on the pyrrolidine-2,5-dione core fragment as candidates for wide-spectrum antiepileptic drugs (AEDs) has been developed and confirmed in our previous research. [10][11][12][13][14] Our most recent data showed that KA-104 (compound 22 in Abram et al 15 ) displayed most favorable efficacy within a series of compounds that were synthetized as hybrids merging the structural fragments of known AEDs, such as ethosuximide (ETX), levetiracetam (LEV), an experimental analgesic BCTC (transient receptor potential vanilloid 1 [TRPV1] antagonist), 16 and compound KA-11, which was identified as a potent anticonvulsant in our earlier studies 11 (Figure 1).…”

“…College in Cracow according to a procedure described elsewhere (see compound 22). 15 The reference AEDs, ETX, lacosamide (LCS), LEV, PGB, and VPA, were purchased from Sigma-Aldrich. 18,19 In the capsaicin-induced nociception model, the animals were pretreated with vehicle (10 mL/kg, negative control) and the dose-response of the investigated compound KA-104 (10, 20, and 30 mg/ kg), PGB (5, 10, and 20 mg/kg), and VPA (100, 150, and 200 mg/kg) was established.…”