Orally active small molecule somatostatin 4 receptor agonists as novel analgesic and antidepressant drug candidates
01/29/2020
Eva Szoke1, Boglarka Kantas1, Eva Borbely1, Agnes Hunyady1, Junaid Ashgar1, Csaba Hetenyi1, Rita Borzsei1, Peter Banhegyi1, János Szolcsányi1, Erika Pintér1, Zsuzsanna Helyes1
1 Department of Pharmacology and Pharmacotherapy of Pécs Medical School, János Szentágothai Research Centre, University of Pécs, Hungary
Background:Somatostatin released from capsaicin-sensitive peptidergic nociceptors at the periphery and GABAergic interneurons in the brain inhibits pain, anxiety and depression. Its sst4 receptor is not involved in the endocrine actions, but it has potent analgesic and anti-depressant functions proposing drug developmental perspectives. Since it is expressed in pain and mood-related brain regions, we investigated the effects of our novel small molecule sst4 receptor agonists in mouse models of neuropathic pain and depression-like behavior. Methods: Sst4 receptor binding of our pirrolo-pirimidine compounds was determined in silico, activation by the gamma-GTP-binding, cAMP inhibition and beta-arrestin activation assay on sst4-expressing CHO cells. The effects of 4 most potent and efficacious agonists were tested on partial sciatic nerve ligation-induced traumatic mononeuropathic hyperalgesia, spontanepus locomotor activity and anxiety in the open field and elevated plus maze tests, depression-like behaviour in the tail suspension test. Results: Our novel compounds bind to the high affinity binding site of the receptor, activate the G-protein binding and inhibit cAMP formation. However, despite the reference sst4 agonists, they do not induce beta-arrestin activation responsible for tolerance upon chronic use. They exert 65-80% maximal antihyperalgesic effects in the neuropathy model after a single oral administration of 100-500 microg/kg doses, as well as significantly inhibit anxiety and depression-like behavior without influencing spontenaous locomotion. Conclusion: Our sst4 agonists are promising drug candidates for neuropathic pain, anxiety and depression that are mediated by common mechanisms and frequently occur as co-morbidities.Support: National Brain Research Program (2017-1.2.1-NKP-2017-00002); GINOP-2.3.2-15-2016-00050 „PEPSYS”; EFOP-3.6.1-16-2016-00004, János Bolyai Fellowship, EFOP-3.6.2-16-2017-00008, 20765/3/2018 FEKUTSTRAT