Summary of the technology
We designed unique ligands targeting the voltage sensor domain (VSD) of two voltage-gated cation channels (VGCC), Kv7.2 and TRPV1 channels. These drugs simultaneously function as openers of Kv7.2 and blockers of TRPV1. They act in vitro and in vivo to depress neuronal hyper-excitability like neuropathic pain.
Project ID : 10-2011-129
We designed unique ligands targeting the voltage sensor domain (VSD) of two voltage-gated cation channels (VGCC), Kv7.2 and TRPV1 channels. These drugs simultaneously function as openers of Kv7.2 and blockers of TRPV1. They act in vitro and in vivo in neuropathic and inflammatory pain models.
Neuropathic pain affects approximately 3-8% of the population worldwide and leads to a large economic and social burden on society. Many patients (40-50%) remain refractory to the existing pharmacological treatment and many promising new drugs have been disappointingly ineffective in clinical trials. A recent study suggests that this lack of successful clinical translation may be due to the “plasticity” of the pain system. Drugs that target just one type of ion channel may fail to relieve neuropathic pain because compensatory changes in any one of other ion channels may circumvent the therapeutic effect. Treatment strategies for neuropathic pain must change towards a systems-based approach involving multi-target drugs and move away from single-target-drugs. In the absence of disease-modifying or curative agents for the management of neuropathic pain, improved analgesic efficacy remains a primary unmet need. It is estimated that only one in four patients with neuropathic pain experiences over 50% pain relief. The pharmaceutical industry has so far struggled to improve current therapeutic options, owing to the complexity of identifying the most appropriate targets to investigate. Currently available drugs also produce several significant side effects such as drowsiness, dizziness and somnolence, which negatively affect patients’ quality of life. Neuropathic pain drug cost is expected to rise from US$2.4 billion in 2010 to peak sales of $3.6 billion by 2020.
Kv7.2/3 and TRPV1 channels were shown to represent key elements of the pain system displaying antagonistic activities, with TRPV1 being a strong trigger of painful stimuli that are dampened by Kv7.2/3. Here we designed unique ligands targeting the voltage sensor domain (VSD) of two voltage-gated cation channels (VGCC), Kv7.2 and TRPV1 channels. These drugs simultaneously function as openers of Kv7.2 and blockers of TRPV1, thereby acting in vitro and in vivo to depress neuronal hyper-excitability like neuropathic and inflammatory pain.
We have designed a set of about 20 initial structurally related ligands (NH14-NH34) and tested them on the two target channels Kv7.2 and TRPV1. Results show that each of these ligands activates Kv7.2 and inhibits TRPV1 channels in the micromolar range as tested in heterologous expression systems. Mutagenesis and docking experiments indicate that these molecules interact with the VSD of Kv7.2 and TRPV1 channels. These initial ligands potently depress neuronal excitability (spike firing) of isolated sensory nociceptive neurons by respectively activating Kv7.2 and inhibiting TRPV1 native currents. Preliminary selectivity experiments indicate that some of the ligands display no significant interaction with the cardiac human Herg channel and exhibit selectivity for Kv7.2 and TRPV1 among other members of Kv7 and TRP channel families. Several of the active ligands, are very efficient in alleviating neuropathic pain induced by mechanical pressure or cold allodynia in the Seltzer rat model and in alleviating inflammatory pain in the model of complete Freund adjuvant (10-30 mg/kg). Remarkably, the active leads have no effects on body temperature as would be expected for an only blocker of TRPV1. Taken together, the results obtained so far with the initial ligands are very promising and prove the feasibility of the technology and the rationale of a dual VSD channel targeting.
Next we plan to use a fragment-based rational chemistry to modify our initial ligands. Based on NH25 design new analogues and identify compounds with the following properties: