AUTHOR=Kántás Boglárka , Szőke Éva , Börzsei Rita , Bánhegyi Péter , Asghar Junaid , Hudhud Lina , Steib Anita , Hunyady Ágnes , Horváth Ádám , Kecskés Angéla , Borbély Éva , Hetényi Csaba , Pethő Gábor , Pintér Erika , Helyes Zsuzsanna 

TITLE=In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 11 - 2020

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.601887

DOI=10.3389/fphar.2020.601887

ISSN=1663-9812

ABSTRACT=Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need.
Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and β-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1000, 2000 µg·kg-1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice.
Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor, activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalisation upon chronic use. They exert 65–80 % maximal anti-hyperalgesic effects in the neuropathy model 1 hour after a single oral administration of 100–500 µg·kg-1 doses.
Conclusion and Implications: The novel orally active compounds show potent and effective SST4 receptor agonism in vitro and in vivo. All four novel ligands proved to be full agonists based on G protein activation, but failed to recruit β-arrestin. Based on their potent antinociceptive effect in the neuropathic pain model following a single oral administration, they are promising candidates for drug development.