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Papers of the Week

2023 Jan 21

Biochem Pharmacol

The heptapeptide somatostatin analogue TT-232 exerts analgesic and anti-inflammatory actions via SST receptor activation: in silico, in vitro and in vivo evidence in mice.


Börzsei R, Borbély É, Kántás B, Hudhud L, Horváth Ádám, Szőke É, Hetényi C, Helyes Z, Pintér E
Biochem Pharmacol. 2023 Jan 21:115419.
PMID: 36693436.


Since the conventional and adjuvant analgesics have limited effectiveness frequently accompanied by serious side effects, development of novel, potent pain killers for chronic neuropathic and inflammatory pain conditions is a big challenge. Somatostatin (SS) regulates endocrine, vascular, immune and neuronal functions, cell proliferation through 5 G protein-coupled receptors (SST-SST). SS released from the capsaicin-sensitive peptidergic sensory nerves mediates anti-inflammatory and antinociceptive effects without endocrine actions via SST. The therapeutic use of the native SS is limited by its diverse biological actions and short plasma elimination half-life. Therefore, SST selective SS analogues could be promising analgesic and anti-inflammatory drug candidates with new mode of action. TT-232 is a cyclic heptapeptide showing great affinity to SST and SST. Here, we report the in silico SST receptor binding mechanism, in vitro binding (competition assay) and cAMP- decreasing effect of TT-232 in SST-expressing CHO cells, as well as its analgesic and anti-inflammatory actions in chronic neuropathic pain and arthritis models using wildtype and SST-deficient mice. TT-232 binds to SST with similar interaction energy (-11.03kcal/mol) to the superagonist J-2156, displaces somatostatin from SST binding (10nM to 30µM) and inhibits forskolin-stimulated cAMP accumulation (EC: 371.6±58.03nmol; E: 78.63±2.636%). Its i.p. injection (100, 200µg/kg) results in significant, 35.7% and 50.4%, analgesic effects upon single administration in chronic neuropathic pain and repeated injection in arthritis models in wildtype, but not in SST-deficient mice. These results provide evidence that the analgesic effect of TT-232 is mediated by SST activation, which might open novel drug developmental potentials. Chemical compounds Chemical compounds studied in this article TT-232 (PubChem CID: 74053735).