(BO/00620/24/5) Támogató: Bolyai János Kutatási Ösztöndíj
The effective treatment of neuropathic pain caused by metabolic or traumatic injury
to the peripheral or central nervous system
is an unsolved clinical problem. Traditional and adjuvant analgesics are limited in
efficacy and often cause serious side effects,
hence there is an unmet medical need for drug candidates with novel mechanism of action.
It is proved that somatostatin, released from capsaicin-sensitive peptidergic sensory
nerve terminals, mediates analgesic and anti-inflammatory effects without
endocrine action via somatostatin receptor subtype 4. The therapeutic use of native
somatostatin is limited, due to the numerous
biological effects mediated by the five somatostatin receptors and its short plasma
half-life time. Therefore, the development of
sst4 selective agonists may be an effective solution for the treatment of neuropathic
pain. In this study the receptor binding and
activation properties of four small molecules were compared by drug-likeness investigation,
pharmacokinetic prediction, molecular docking calculation in silico as well as cAMP
accumulation assay in vitro. Structural comparison including binding patterns,
energies and interacting functional groups of the molecules were compared with that
of endogenous somatostatin and the sst4
superagonist, J-2156. It is known from the literature that the conserved ASP amino
acid of the transmembrane region III of sst
receptors plays a key role in ligand binding. Docking calculations showed that all
compounds interact with the conserved ASP126
of sst4. The cAMP accumulation assay performed in sst4 or sst2 overexpressing Chinese
Hamster Ovary (CHO) cells confirmed
that all molecules have selective effects on the sst4 receptor with comparable potency
to that of the superagonist, J2156. These
results suggest that the tested compounds could be potentially effective in the treatment
of neuropathic pain, although in some
cases, their pharmacokinetic predicted properties require further investigation to
determine their penetration into the central
nervous system.
Acknowledgement: The work was supported by Richter Gedeon Talentum Foundation, Bolyai
János Research Scholarship of
Hungarian Academy of Sciences.
