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=11
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, 1,000, 2,000 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 and 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 internalization upon chronic use. They exert 65–80% maximal anti-hyperalgesic effects in the neuropathy model 1 h 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.