HNK analog identification and characterization as an approach to non-opioid analgesics

Approximately 20% of the population suffering from daily pain over an extended period. There are multiple types of chronic pain, including neuropathic, nociceptive, musculoskeletal, inflammatory, psychogenic, and mechanical. Currently, the most effective treatment for chronic pain is opioids, with other medications such as tricyclic antidepressants and gabapentin being less effective. Considering the problems and side-effects with extended opioid treatment, the search for additional analgesics for the treatment of chronic neuropathic and nociceptive pain is a high priority. A recently explored alternative therapy to opioids is ketamine (RS-Ket), an NMDA receptor antagonist. RS-Ket is a dissociative anesthetic that provides significant pain reduction, but also produces adverse outcomes, especially psychotomimetic effects through its action as an NMDA antagonist. We and others have recently demonstrated that the ketamine metabolite 2R6R-hydroxynorketamine (2R6R-HNK) lacks RS-Ket-like NMDA antagonist activity but still has antinociceptive activity, as well as other potential benefits for psychiatric disorder. Potential mechanisms for this effect include activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and inhibition of synthesis of D-serine (D-Ser), an NMDA receptor co-agonist. We have demonstrated that 2R6R-HNK can reduce D-ser levels in pheochromocytoma, PC-12 cells. Increased D-Ser concentrations result in elevated NMDA receptor activity and are associated with neuroinflammation and pain windup, without the associated psychotomimetic activity. Thus, reducing D-Ser concentration in the brain represents a potential innovative and impactful target that could mediate analgesia without inducing unwanted side effects. Other direct evidence demonstrates that inhibition of AMPA receptor with NBQX blocks the anti-allodynic activity of 2R6R-HNK, suggesting involvement of AMPA receptors in addition to or potentially rather than D-Ser. Using the attenuation of D-Ser synthesis as the functional outcome, we created a pharmacophore model and designed and synthesized 36 proprietary HNK-analogs, named HNK-SPs (SP for Spirify). Several of these compounds were tested and found to have antiallodynic activity in spared nerve injury (SNI) mice. Our overarching hypothesis is that the analgesic activity of 2R6R-HNK and analogs is due to non-mu, non-NMDA actions and will provide a scaffold for novel analgesics with fewer side effects. In this grant we will test a subset of these compounds in SNI and Complete Freund’s Adjuvant (CFA) models of chronic neuropathic and inflammatory pain, respectively, using both reflexive (von Frey filaments and hotplate to measure mechanical and heat pain) and non-observational (conditioned place preference and wheel running to measure affective and ongoing pain states) methods of analysis. Initial PK and ADME studies will be conducted to guide the discovery process. There are currently no optimal treatments for chronic pain. Accordingly, development of an effective and safe non-opioid analgesic is a high priority. These studies should lead to the development of novel non-opioid, non-NMDA receptor mediated analgesics for the treatment of chronic pain.