Yiannaki, E; (2016) Development of Small Molecule Iminodihydroquinolines as New Generation Pain Therapeutics. Doctoral thesis , UCL (University College London).

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Abstract

Acute and chronic pain is a common symptom of many diseases. Therapy is often not effective or is associated with significant adverse effects; the development of novel analgesic drugs with high therapeutic index is an urgent unmet clinical need. Several lines of evidence converge to show that pain is mostly signalled by activity in peripheral unmyelinated (C) or thinly myelinated (Aδ) sensory fibres, called nociceptors. A drug selectively affecting the conduction of nociceptors without interfering with the function of other peripheral nerve fibres (Aα, Aβ, Aγ) or cells in the central nervous system and heart would be an ideal pain therapeutic. We recently discovered that WIN17317-3, a small molecule iminodihydroquinoline, previously reported as a high affinity, state-dependent sodium channel (Nav) blocker, can produce such a selective nociceptor block. Specifically, WIN17317-3 blocks the conduction of nociceptive C-fibers, leaving A-fibers, mainly involved in motor control and non-painful sensations, largely unaffected. To the best of our knowledge no other small molecule has been reported to exhibit such a selective blocking effect. This thesis describes the development of iminodihydroquinolines as novel analgesic candidate drugs with selective action on pain-signalling neurons. Following the traditional “hit” to “lead” drug discovery approach, a library of WIN17317-3 derivatives was synthesized. The compounds were screened using state of the art electrophysiological assays to determine their effects on the human Nav1.7 isoform, and selected structures were further characterized in a functional assay using rodent peripheral sensory nerves. Voltage-gated sodium channels are responsible for the generation and propagation of action potentials in all electrically excitable cells; Nav1.7 channels are highly expressed in nociceptors, but are sparsely expressed or absent in non-nociceptive neurons. The iminodihydroquinolines described, were found to potently inhibit Nav1.7 channels and nociceptor conduction leaving non-nociceptive fibers largely unaffected. A selected lead preclinical drug candidate was subjected to in vivo pharmacokinetic profiling and toxicity studies in rodents. The results suggest that iminodihydroquinolines may be suitable analgesic drugs for topical, local, or regional administration with a wide safety margin. To achieve selective blockade of nociceptors clinically without interfering with the action of motor neurons would be a major breakthrough for the treatment of pain disorders and anesthesia.

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