The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder

Abstract

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention De cit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that de cient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient strati cation, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function.

Design, Synthesis, and Structure–Activity Relationship Studies of Novel GPR88 Agonists (4-Substituted-phenyl)acetamides Based on the Reversed Amide Scaffold

“…The combined organic layers were washed with brine (3 × 30 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel using 0−10% EtOAc in hexanes to afford 48 (3.56 g, 86% yield) as a light-yellow oil: 1 H NMR (300 MHz, CDCl 3 ): δ 7.56−7.31 (m, 2H), 2H),3.64 (ddd,J = 15.6,8.9,6.3 Hz,2H), 2.03−1.73 (m, 1H), 1.55−1.13 (m, 4H), 0.97 (d, J = 6.7 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ 159. 3, 138.2, 117.1, 82.6, 73.5, 35.9, 33.0, 20.2, 17.2, 14.6; MS (ESI) m/z: 305.2 [M + H] + .…”

“…The combined organic layers were washed brine (2 × 50 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel using 0−20% EtOAc in hexanes to afford 49 (1.80 g, 99% yield) as a colorless oil: 1 H NMR (300 MHz, CDCl 3 ): δ 7.28 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.48 (s, 1H), 3.85−3.66 (m, 5H), 2.02−1.85 (m, 1H), 1.50−1.12 (m, 13H), 0.99 (t, J = 5.3 Hz, 3H), 0.96−0.85 (m, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ 169. 3, 167.5, 159.2, 130.3, 125.0, 114.6, 82.2, 73.2, 58.1, 52.5, 35.8, 32.9, 27.9, 20.0, 17.0, 14.3 oxy]phenyl}-3-oxopropanoic Acid (50).…”

“…The combined organic layers were washed with brine (2 × 10 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel using 0−100% EtOAc in hexanes to afford diastereomeric mixture 51 (257 mg, 31% yield) as a colorless oil: 1 H NMR (300 MHz, CDCl 3 ): δ 7.41−7.15 (m, 6H), 7.04 (dd, J = 19.6, 7.9 Hz, 1H), 6.86 (t, J = 9.2 Hz, 2H), 5.11 (p, J = 7.0 Hz, 1H), 4.47 (s, 1H), 3.83−3.66 (m, 5H), 2.01−1.84 (m, 1H), 1.46 (t, J = 7.4 Hz, 4H), 1.41−1.12 (m, 3H), 1.07 (br s, 1H), 1.00 (dd, J = 6.7, 2.1 Hz, 3H), 0.92 (t, J = 6.9 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ 171. 5, 166.6, 159.4, 159.4, 143.0, 142.9, 129.4, 129.4, 128.6, 128.6, 127.3, 127.3, 126.0, 125.8, 125.7, 115.1, 115.0, 73.3, 57.7, 57.6, 52.6, 49.0, 49.0, 35.8, 32.9, 21.9, 21.8, 20.0, 17.0, 14.3 52).…”

“…The absolute stereochemistry of 10 was confirmed by an asymmetric synthesis shown in Scheme 2 and assigned as the (S,R)isomer, and therefore 9 was assigned as the (R,R)-isomer. Compound 9: 1 H NMR (300 MHz, CDCl 3 ): δ 7.36−7.22 (m, 5H), 7.19−7.10 (m, 2H), 6.96−6.80 (m, 2H), 5.66 (d, J = 7.9 Hz, 1H), 5.21−5.01 (m, 1H), 4.20−4.00 (m, 1H), 3.81 (dd, J = 8.9, 5.8 Hz, 1H), 3.77−3.66 (m, 2H), 3.59 (dd, J = 8.9, 4.4 Hz, 1H), 3.48 (dd, J = 8.8, 4.1 Hz, 1H), 2.07−1.80 (m, 1H), 1.55−1.15 (m, 7H), 1.02 (d, J = 6.7 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ 173. 2, 159.0, 142.8, 129.5, 128.7, 128.4, 127.4, 126.0, 115.2, 73.3, 65.3, 53.4, 48.8, 35.8, 32.9, 21.5, 20. 143.1, 129.6, 128.6, 128.3, 127.3, 125.7, 115.1, 73.3, 65.2, 53.4, 48.9, 35.8, 32.9, 22.0, 20.0, 17.0, 14.3 54a).…”

“…2, 159.0, 142.8, 129.5, 128.7, 128.4, 127.4, 126.0, 115.2, 73.3, 65.3, 53.4, 48.8, 35.8, 32.9, 21.5, 20. 143.1, 129.6, 128.6, 128.3, 127.3, 125.7, 115.1, 73.3, 65.2, 53.4, 48.9, 35.8, 32.9, 22.0, 20.0, 17.0, 14.3 54a). The procedure for the synthesis of 48 was followed starting with 53 to afford ether 54a (70% yield) as a colorless oil: 1 H NMR (300 MHz, CDCl 3 ): δ 7.20− 7.10 (m, 2H), 6.92−6.72 (m, 2H), 3.85−3.62 (m, 5H), 3.55 (s, 2H), 2.04−1.79 (m, 1H), 1.59−1.08 (m, 4H), 1.00 (d, J = 6.7 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ 172. 4, 158.5, 130.2, 125.8, 114.6, 73.3, 51.9, 40.3, 35.8, 32.9, 20.0, 17.0, 14.3 54b).…”