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

• Main Authors: Boglárka Kántás (Author), Éva Szőke (Author), Rita Börzsei (Author), Péter Bánhegyi (Author), Junaid Asghar (Author), Lina Hudhud (Author), Anita Steib (Author), Ágnes Hunyady (Author), Ádám Horváth (Author), Angéla Kecskés (Author), Éva Borbély (Author), Csaba Hetényi (Author), Gábor Pethő (Author), Erika Pintér (Author), Zsuzsanna Helyes (Author)
• Format: Book
• Published: Frontiers Media S.A., 2021-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2020.601887
• Keywords: neuropathic pain; drug discovery; G protein coupled receptor; somatostatin; somatostatin receptor subtype 4; molecular; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 11 (2021)

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.