Metabotropic glutamate receptor 5 (mGlu5) is an excitatory GQ coupled G protein-coupled receptor, which is mainly expressed in the postsynaptic region of neurons. Besides, they regulate cellular signal transduction and synaptic transmission to the main excitatory neurotransmitter L-glutamate (L-glutamate). Amino acid L-glutamate is the main excitatory neurotransmitter in the central nervous system, which can activate ionic and metabolic glutamate receptors. Moreover, glutamatergic neurotransmission involves most aspects of normal brain function. Furthermore, the mGlu5 receptor is widely in the whole central nervous system (CNS). The metabotropic glutamate receptor is a family of G protein-coupled receptors. Specifically, negative allosteric modulators (NAM) are ligands that reduce the effects of positive agonists, endogenous activators, or antagonists.

Selective antagonists and negative allosteric modulators of mGluR5 have shown anti-anxiety, anti-depression, and anti-addiction effects in animal studies. Nonetheless, mGluR5 antagonists have hepatoprotective effects and have the potential for inflammatory and neuropathic pain. Today, we will introduce an advanced and orally active mGlu5 NAM, HTL14242.

HTL14242 is an Orally Active mGlu5 NAM.

At first, HTL14242 (HTL0014242) is an advanced and orally active mGlu5 NAM with a pKi and a pIC50 of 9.3 and 9.2, respectively. Obviously, HTL14242 has the potential for the research of Parkinson’s disease.

Secondly, HTL14242 is stable in rat plasma, inactive at the hERG ion-channel. Particularly, HTL14242 has a clean profile in vitro assays of cytotoxicity in HepG2 cells with the TC50 is >90 μM.

Thirdly, HTL14242 with 1-10 mg/kg by oral demonstrates an excellent, dose-dependent occupancy of mGlu5 receptors. And it has an estimated ED50 of 0.3 mg/kg. Interestingly, HTL14242 exhibits an oral PK Profile, the t1/2, AUCinf, and F% are 6.5 hours, 3946 ng/h/mL, and 80%, respectively in dogs.

Finally, HTL14242 is an orally active mGlu5 NAM.


Kirstie A Bennett, et al. Adv Pharmacol. 2020;88:35-58.