The Heptapeptide Somatostatin Analogue TT-232 Exerts Analgesic and Anti-Inflammatory Actions Via SST4 Receptor Activation: in Silico, in Vitro and in Vivo Evidence in Mice

Rita Borzsei,Eva Borbely,Boglarka Kantas,Lina Hudhud,Adam Horvath,Eva Szoke,Csaba Hetenyi,Zsuzsanna Helyes,Erika Pinter

British Journal Of Pharmacology（2023）SCI 2区SCI 1区

Cited 1|Views44

Abstract

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 Gi protein-coupled receptors (SST1-SST5). SS released from the capsaicin-sensitive peptidergic sensory nerves mediates anti-inflammatory and antinociceptive effects without endocrine actions via SST4. The therapeutic use of the native SS is limited by its diverse biological actions and short plasma elimination half-life. Therefore, SST4 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 SST4 and SST1. Here, we report the in silico SST4 receptor binding mechanism, in vitro binding (competition assay) and cAMPdecreasing effect of TT-232 in SST4-expressing CHO cells, as well as its analgesic and anti-inflammatory actions in chronic neuropathic pain and arthritis models using wildtype and SST4-deficient mice. TT-232 binds to SST4 with similar interaction energy (-11.03 kcal/mol) to the superagonist J-2156, displaces somatostatin from SST4 binding (10 nM to 30 mu M) and inhibits forskolin-stimulated cAMP accumulation (EC50: 371.6 +/- 58.03 nmol; Emax: 78.63 +/- 2.636 %). Its i.p. injection (100, 200 mu g/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 SST4-deficient mice. These results provide evidence that the analgesic effect of TT-232 is mediated by SST4 activation, which might open novel drug developmental potentials. Chemical compounds Chemical compounds studied in this article TT-232 (PubChem CID: 74053735).

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In silico modelling,Competition binding assay,cAMP assay,Neuropathic pain,Arthritis,Sciatic nerve ligation

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