J-2156 is a Selective SST4 Receptor Agonist

The somatostatin receptor is the receptor of the ligand somatostatin, especially in the postsynaptic response to the costimulation/activation of the NMDA receptor. Specifically, somatostatin is a small neuropeptide related to neural signals. Besides, Somatostatin acts in many parts to inhibit the release of many hormones and other secreted proteins. Moreover, somatostatin, also known as growth hormone release inhibitory factor (SRIF), has many physiological functions. In addition, SRIF acts as a regulator of neuronal activity and may act as a neurotransmitter. A series of G protein-coupled receptors (GPCR) mediated the wide range of physiological functions of SRIF. GPCR includes five different receptor subtypes, called sst1 to sst5.

Furthermore, Somatostatin receptor (SSTR) is expressed in normal and cancer tissues. The activation of SSTR usually leads to the inhibition of cell proliferation, so somatostatin analog (SSA) has been used in cancer treatment. Here, we will introduce a selective SST4 receptor agonist, J-2156.

J-2156 is a Selective SST4 Receptor Agonist.

First of all, J-2156 is a selective SST4 receptor agonist with IC50s of 0.05 nM and 0.07 nM for human and rat SST4 receptors, respectively. Meanwhile, J-2156 has anti-inflammatory activity. J-2156 is used for the relief of mechanical allodynia and mechanical hyperalgesia in the ipsilateral hind paws in rats.

In the second place, J-2156 binds with nanomolar affinity to the human somatostatin receptor subtype 4 (hsst4: Ki=1.2 nM). Nonetheless, it is over 400-fold subtype-selective against the other somatostatin receptors (hsst1: Ki=0.5 μM; hsst2: Ki>5 μM; hsst3: Ki=1.4 μM; and hsst5: Ki=0.54 μM) in Chinese hamster ovary (CHO) cells.

Last but not the least, J-2156 with 1-10 mg/kg by i.p. of single bolus doses has an anti-allodynic effect on ipsilateral and contralateral in BCIBP-rats. Importantly, a single bolus dose of J-2156 at 10 mg/kg reduced pERK expression levels in the lumbar spinal dorsal horn of BCIBP-rats. Particularly, the ED50 of J-2156 for the relief of mechanical allodynia and mechanical hyperalgesia in the ipsilateral hind paws was 3.7 and 8.0 mg/kg by IP, respectively.

All in all, J-2156 is a highly potent, selective SST4 receptor agonist.

References:

Shenoy PA, et al. Front Pharmacol. 2018 May 15;9:495.