Novel Drugs for the Treatment of Chronic Pain (APP1082570)

Project Member(s): Rawling, T.

Funding or Partner Organisation: National Health & Medical Research Council (NHMRC Project Grants)

Start year: 2015

Summary: Chronic pain is a major global health, economic and social problem. In 2007, the economic burden of unrelieved persistent pain in Australia was $34 billion and it continues to escalate. Current drugs used to manage chronic pain are only effective in s small proportion of patients and produce modest reduction in pain scores. Hence, there exists an unmet need for new analgesics that effectively reduce chronic pain. Diminished glycinergic transmission in the dorsal horn of the spinal cord has recently been identified as an important CNS mechanism underlying chronic pain. Drugs that can enhance dysfunctional glycinergic transmission in neuropathic pain, and in particular glycine transporter inhibitors, are therefore widely recognised as potential chronic pain therapeutics. The glycine transporter GlyT2 has emerged as an attractive target as it expression pattern is restricted to the spinal cord and brain stem. The aim of this project is to develop potent and selective GlyT2 inhibitors using a novel glycine-lipid conjugate drug scaffold we recently identified. A large series of conjugates will be synthesised and assayed for GlyT2 inhibitory activity. Molecular dynamic simulation will be used to understand drug binding modes and aid drug design. The most promising drug candidates will be assessed in in vivo models of pain.

Publications:

Wilson, BS, Peiser-Oliver, J, Gillis, A, Evans, S, Alamein, C, Mostyn, SN, Shimmon, S, Rawling, T, Christie, MJ, Vandenberg, RJ & Mohammadi, SA 2022, 'Peripheral Administration of Selective Glycine Transporter-2 Inhibitor, Oleoyl-D-Lysine, Reverses Chronic Neuropathic Pain but Not Acute or Inflammatory Pain in Male Mice', Journal of Pharmacology and Experimental Therapeutics, vol. 382, no. 3, pp. 246-255.
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Wilson, KA, Mostyn, SN, Frangos, ZJ, Shimmon, S, Rawling, T, Vandenberg, RJ & O’Mara, ML 2021, 'The allosteric inhibition of glycine transporter 2 by bioactive lipid analgesics is controlled by penetration into a deep lipid cavity', Journal of Biological Chemistry, vol. 296, pp. 100282-100282.
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Gallagher, CI, Sheipouri, D, Shimmon, S, Rawling, T & Vandenberg, RJ 2020, 'Identification of N-acyl amino acids that are positive allosteric modulators of glycine receptors', Biochemical Pharmacology, vol. 180, pp. 114117-114117.
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Winters, BL, Rawling, T, Vandenberg, RJ, Christie, MJ, Bhola, RF & Imlach, WL 2018, 'Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord', British Journal of Pharmacology, vol. 175, no. 12, pp. 2337-2347.
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Mostyn, SN, Carland, JE, Shimmon, S, Ryan, RM, Rawling, T & Vandenberg, RJ 2017, 'Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2', ACS Chemical Neuroscience, vol. 8, no. 9, pp. 1949-1959.
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Keywords: chronic pain, glycine transporters, lipids, glycine

FOR Codes: Human Pharmaceutical Treatments (e.g. Antibiotics), Pharmacology and Pharmaceutical Sciences, Human pharmaceutical treatments

Acknowledgement of Country

UTS acknowledges the Gadigal people of the Eora Nation, the Boorooberongal people of the Dharug Nation, the Bidiagal people and the Gamaygal people, upon whose ancestral lands our university stands. We would also like to pay respect to the Elders both past and present, acknowledging them as the traditional custodians of knowledge for these lands.