Oral Presentation 11th Annual Conference of the International Chemical Biology Society 2022

Discovery of dual action bioactive lipids that stimulate glycine receptors and inhibit glycine transporters: potential new analgesics for neuropathic pain (#14)

Robert J Vandenberg 1 , Casey I Gallagher 1 , Zachary J Frangos 1 , Susan Shimmon 2 , Christopher L Cioffi 3 , Tristan Rawling 2
  1. University of Sydney, Sydney, NSW, Australia
  2. School of Mathematical and Physical Sciences, University of Technology, Sydney, Sytdney, NSW, Australia
  3. Organic Chemistry, Rensselaer Polytechnic Institute, Albany, New York, USA

Neuropathic pain is poorly treated by current therapeutics and there is an urgent need for new drugs that target different mechanisms. Glycine neurotransmission in the spinal cord plays a key role in distinguishing between innocuous and painful stimuli and a common features of neuropathic pain is a reduction in glycine neurotransmission. We have sought to discover new drugs that have the capacity to stimulate glycine neurotransmission to restore normal pain sensation. Due to the complex nature of chronic pain conditions, one approach is to design therapeutics which act at multiple targets. In this study a library of phenylene containing bioactive lipids were designed and their actions characterised at glycine transporters and receptors. Introducing a phenylene ring into the tail of lipids containing either glycine and lysine head groups was found to significantly enhance potentiation of glycine receptors. 8-8 Ortho-phenylene glycine potentiates the EC5 activation of GlyRα1 by 1500 % with an EC50 of 664 nM. It also significantly shifts the glycine dose response and reduces the EC50 of glycine by 58%. Phenylene lipids were also found to inhibit GlyT2. Those with a lysine head group were found to produce potent inhibition, with 8-8 meta-phenylene L-lysine inhibiting the transporter with an IC50 of 32 nM. 8-8 ortho-phenylene lysine inhibits GlyT2 with an IC50 of 192 nM, and potentiates the EC5 activation of GlyRs by up to 335 % at 1 µM. When tested in a dual-expression system consisting of both GlyT2 and GlyRα1 expressed in a ratio of 10:1, 8-8 ortho-phenylene lysine reduces the EC50 for glycine activation of GlyRs by 69 %, which was greater than the single-target lipids 8-8 meta-phenylene lysine and 8-8 ortho-phenylene glycine, which reduced the EC50 of glycine by 33% and 44% respectively. This suggests that the synergistic effects of a dual-acting modulator causes greater enhancement in glycinergic activity compared to single-target modulators with greater efficacy and are likely to produce greater analgesia in vivo.