Abstract
Opiranserin (VVZ-149) is a novel non-opioid, non-steroidal intravenous analgesic with triple antagonistic activity at glycine transporter 2 (GlyT2), purine 2 receptor 3 (P2X3), and serotonin receptor (5-HT2A). Its half-maximal inhibitory concentrations are 0.86, 0.87, and 1.3 μM for GlyT2, P2X3, and 5-HT2A, in the order of strength of inhibition. GlyT2 is a sodium- and chloride-dependent transporter that recycles Gly from the synaptic cleft into the presynaptic Gly terminals in the spinal cord, brainstem, and cerebellum. Inhibition of GlyT2 allows Gly to remain longer in the synaptic cleft and bind to postsynaptic Gly receptors, thereby enhancing inhibitory neurotransmission and potentially relieving chronic neuropathic pain. P2X3 antagonists are being investigated for refractory chronic cough, overactive bladder, endometriosis, and chronic pain, especially diabetic neuropathic pain. A 5-HT2A antagonist is used to treat psychiatric disorders, cardiovascular disorders, and nausea/vomiting. It also attenuates pain-related behavior and suppresses 5-HT2A expression in the dorsal root ganglion. Based on the triple analgesic mechanisms, opiranserin is mainly suitable for neuropathic pain which can contribute to pain chronification and partially helpful for nociceptive pain. Among the three proposed analgesic targets of opiranserin, published studies have focused on the effects mediated by GlyT2 and 5-HT2A antagonism, whereas the contribution of P2X3 antagonism has not been adequately investigated. Therefore, therapeutic effects and adverse events related to P2X3 cannot be fully anticipated. The major clinical concern is that opiranserin cannot be added to disposable intravenous patient-controlled analgesia devices due to their limited volume. Repeated administration may accumulate its active metabolite, VVZ-368 (N-desmethyl-VVZ-149).