Discovery of the First Potent and Orally Available Agonist of the Orphan G-Protein-Coupled Receptor 52

Abstract

G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds 2a and 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-methoxyethyl)benzamide 7m showed potent activity (pEC50 = 7.53 ± 0.08) and good pharmacokinetic properties. Compound 7m significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function.

FTBMT, a Novel and Selective GPR52 Agonist, Demonstrates Antipsychotic-Like and Procognitive Effects in Rodents, Revealing a Potential Therapeutic Agent for Schizophrenia

“…Previous studies have highlighted the potential role of GPR52 in targeting the positive symptoms of schizophrenic. Evidence for this hypothesis comes from behavioral studies of methamphetamine responsiveness using GPR52 transgenic mice and the GPR52 agonist compound 7m (Komatsu et al, 2014;Setoh et al, 2014); however, there is a lack of biochemical evidence to support and understand these behavioral data. In the current study, we used biochemical analyses to demonstrate that FTBMT activated cAMP signaling in vitro and in vivo.…”

“…EC 50 values were analyzed using nonlinear regression analyses with GraphPad PRISM software (GraphPad Software Inc., San Diego, CA). In the cAMP assay using recombinant CHO cells, the response at 1 mM of N-(2-hydroxyethyl)-3-(2-(3-(trifluoromethyl)benzyl)-1-benzofuran-4-yl)benzamide (compound 7a) was used as the 100% control as described previously (Setoh et al, 2014).…”

“…In such a situation, we have been trying to reveal its biologic function. Reserpine, an antihypertensive agent (Fraser, 1996), and a series of small compounds raise intracellular cAMP levels in recombinant cells expressing GPR52, which indicated that GPR52 is coupled to a Gs protein (Komatsu et al, 2014;Setoh et al, 2014). Given that D2R is a Gi-coupled receptor, which decreases intracellular cAMP levels when activated, the stimulation of GPR52 may counteract D2R signaling of the medium spiny neurons in the striatum and Nac.…”

“…Given that D2R is a Gi-coupled receptor, which decreases intracellular cAMP levels when activated, the stimulation of GPR52 may counteract D2R signaling of the medium spiny neurons in the striatum and Nac. Indeed, the systemic administration of a GPR52 agonist, 3-(2-(3-chloro-5-fluorobenzyl)-1-benzothiophen-7-yl)-N-(2-methoxyethyl)benzamide (compound 7m), and overexpression of GPR52 attenuate methamphetamineinduced hyperactivity in mice (Komatsu et al, 2014;Setoh et al, 2014). Moreover, compound 7m did not produce a cataleptic response; however, the underlying mechanism of action for the antipsychotic-like activity of GPR52 agonists, which do not induce catalepsy, and their effects on cognitive function remain unknown.…”

Novel Therapeutic GPCRs for Psychiatric Disorders

“…More intriguingly, GPR52 shows a unique expression pattern where this receptor is expressed in almost all of the D2 expressing-MSNs of the basal ganglia while largely expressed in the D1 expressing neurons in the medial prefrontal cortex ( Figure 1 and Figure 2 ). This raises the possibility that the GPR52 activation improves positive symptoms of schizophrenia by antagonizing the Gi/o-coupled D2 receptor activity in striatopallidal MSNs and improves schizophrenic negative symptoms and cognitive impairment through enhancement of the NMDA receptor activity via protein kinase A (PKA) in prefrontal cortical neurons, as seen in D1 receptor-NMDA signal transduction ( Figure 2 ) [ 62 , 63 , 64 ].…”