In:
Frontiers in Pharmacology, Frontiers Media SA, Vol. 11 ( 2021-1-27)
Abstract:
Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST 4 ) without influencing endocrine functions. Therefore, SST 4 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, SST 4 -linked G protein activation and β-arrestin activation on stable SST 4 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 SST 4 the receptor and activate the G protein. However, unlike the reference SST 4 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 SST 4 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.
Type of Medium:
Online Resource
ISSN:
1663-9812
DOI:
10.3389/fphar.2020.601887
DOI:
10.3389/fphar.2020.601887.s001
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2021
detail.hit.zdb_id:
2587355-6
SSG:
15,3
