Novel Functionalized Amino Acids as Inhibitors of GABA Transporters with Analgesic Activity

Abstract

Neuropathic pain resistance to pharmacotherapy has encouraged researchers to develop effective therapies for its treatment. γ-Aminobutyric acid (GABA) transporters 1 and 4 (mGAT1 and mGAT4) have been increasingly recognized as promising drug targets for neuropathic pain (NP) associated with imbalances in inhibitory neurotransmission. In this context, we designed and synthesized new functionalized amino acids as inhibitors of GABA uptake and assessed their activities toward all four mouse GAT subtypes (mGAT1–4). According to the obtained results, compounds 2 RS ,4 RS - 39c (pIC 50 (mGAT4) = 5.36), 50a (pIC 50 (mGAT2) = 5.43), and 56a (with moderate subtype selectivity that favored mGAT4, pIC 50 (mGAT4) = 5.04) were of particular interest and were therefore evaluated for their cytotoxic and hepatotoxic effects. In a set of in vivo experiments, both compounds 50a and 56a showed antinociceptive properties in three rodent models of NP, namely, chemotherapy-induced neuropathic pain models (the oxaliplatin model and the paclitaxel model) and the diabetic neuropathic pain model induced by streptozotocin; however compound 56a demonstrated predominant activity. Since impaired motor coordination is also observed in neuropathic pain conditions, we have pointed out that none of the test compounds induced motor deficits in the rotarod test.

Analysis of Binding Determinants for Different Classes of Competitive and Noncompetitive Inhibitors of Glycine Transporters

“…MD simulations were performed in NAMD 2.13 using the CHARMM36m force field. Complexes were positioned in the membrane using the OPM server, and input files for MD simulations were prepared with the CHARMM-GUI online server following the same settings mentioned in our previous papers [ 53 , 61 , 62 ]. The system was equilibrated via a six-step protocol, and MD simulations were run at 303.15 K with a time step of 2 fs and a total duration of 50 ns.…”

Understanding the function of the GABAergic system and its potential role in rheumatoid arthritis

“…In the presence of reduced endogenous GABAergic tone, the GABA-B receptor agonist baclofen exerts an anti-injury sensory effect and releases GABA from the cortical precursors of GABAergic interneurons transplanted into the medial ganglion bulge, ultimately reversing neuropathic abnormal pain ( 105 ). GAT proteins are highly dynamic in different cell types and are responsible for the recycling and reuptake of GABA, thereby terminating inhibitory signaling ( 106 ). Studies have reported that inhibition of GAT reuptake enhances GABAergic neurotransmission and has an inhibitory effect on the release of aspartate and glutamate in the dorsal spinal cord, thereby inhibiting the release of pro-nociceptive neurotransmitters to achieve analgesia ( 107 ).…”

Spinal Cord Injury Provoked Neuropathic Pain and Spasticity, and Their GABAergic Connection

“…17,88 In a recent study, novel functionalized amino acids that were designed and synthesized exhibited inhibitory effects on mGAT4 and mGAT2 transporters and showed analgesic effects in preclinical studies of 3 different NP mod-els. 88 Similarly, in another report, novel compounds inhibiting mouse GABA transporters (mGAT3/4), showed an antiallodynic effect by making GABA more available in diabetic and oxaliplatin-induced NP models. 89 Also, GAT-1 inhibitor NNC-711 and GAT-3 inhibitor SNAP-5114, by decreasing the amplitude of pain fibers mediated excitatory postsynaptic currents produced analgesia in NP mice models.…”

“…Although tiagabine is the only clinically approved GAT inhibitor for NP, several molecules and drugs are under investigation for the same [ 17 , 88 ]. In a recent study, novel functionalized amino acids that were designed and synthesized exhibited inhibitory effects on mGAT4 and mGAT2 transporters and showed analgesic effects in preclinical studies of 3 different NP models [ 88 ].…”

“…Although tiagabine is the only clinically approved GAT inhibitor for NP, several molecules and drugs are under investigation for the same [ 17 , 88 ]. In a recent study, novel functionalized amino acids that were designed and synthesized exhibited inhibitory effects on mGAT4 and mGAT2 transporters and showed analgesic effects in preclinical studies of 3 different NP models [ 88 ]. Similarly, in another report, novel compounds inhibiting mouse GABA transporters (mGAT3/4), showed an antiallodynic effect by making GABA more available in diabetic and oxaliplatin-induced NP models [ 89 ].…”