Abstract
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.
Highlights
Targeting somatostatin receptors as novel analgesic and antiinflammatory drug developmental approaches has emerged after our team discovered that somatostatin was released from the activated capsaicin-sensitive peptidergic sensory nerve endings into the systemic circulation which leads to anti-inflammatory and anti-hyperalgesic actions at distant parts of the body (Pintér et al, 2006; Szolcsanyi et al, 2011; Pintér et al, 2014; Schuelert et al, 2015; Shenoy et al, 2018; Hernández et al, 2020; Kuo et al, 2020)
There is an ionic interaction between Asp90 on transmembrane domain 3 (TM3) and tertiary amine group of Compound 2
It is presumed based on site-directed mutagenesis studies that an ionic interaction between Lys9 of endogenous peptide and the conserved aspartic acid on TM3 of all SST receptors has a crucial role in ligand binding and receptor activation (Kaupmann et al, 1995; Nehrung et al, 1995; Ozenberger and Hadcock, 1995; Chen et al, 1999; Liu et al, 2012)
Summary
Targeting somatostatin receptors as novel analgesic and antiinflammatory drug developmental approaches has emerged after our team discovered that somatostatin was released from the activated capsaicin-sensitive peptidergic sensory nerve endings into the systemic circulation which leads to anti-inflammatory and anti-hyperalgesic actions at distant parts of the body (Pintér et al, 2006; Szolcsanyi et al, 2011; Pintér et al, 2014; Schuelert et al, 2015; Shenoy et al, 2018; Hernández et al, 2020; Kuo et al, 2020). In addition to the peripheral nervous system, the SST4 receptor is present in several central nervous system regions involved in the regulation in pain, such as the spinal cord, hippocampus and amygdala (Schreff et al, 2000; Selmer et al, 2000a; Selmer et al, 2000b) All these data provide strong proof of concept that small molecule non-peptide SST4 receptor agonists are promising drug candidates for novel analgesic development. Purpose and Experimental Approach: Here, we examined the in silico binding, SST4linked 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
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