The GPR88 agonist RTI‐13951‐33 reduces alcohol drinking and seeking in mice

Abstract

GPR88 is an orphan G‐protein‐coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain‐penetrant agonist RTI‐13951‐33 on several alcohol‐related behaviours in the mouse. In the intermittent‐access‐two‐bottle‐choice paradigm, the compound reduced excessive voluntary alcohol drinking, while water drinking was intact. This was observed for C57BL/6 mice, as well as for control but not Gpr88 knockout mice, demonstrating efficacy and specificity of the drug in vivo. In the drinking‐in‐the‐dark paradigm, RTI‐13951‐33 also reduced binge‐like drinking behaviour for control but not Gpr88 knockout mice, confirming the alcohol consumption‐reducing effect and in vivo specificity of the drug. When C57BL/6 mice were trained for alcohol self‐administration, RTI‐13951‐33 decreased the number of nose‐pokes over a 4‐h session and reduced the number of licks and bursts of licks, suggesting reduced motivation to obtain alcohol. Finally, RTI‐13951‐33 did not induce any place preference or aversion but reduced the expression of conditioned place preference to alcohol, indicative of a reduction of alcohol‐reward seeking. Altogether, data show that RTI‐13951‐33 limits alcohol intake under distinct conditions that require consummatory behaviour, operant response or association with contextual cues. RTI‐13951‐33 therefore is a promising lead compound to evaluate GPR88 as a therapeutic target for alcohol use disorders. More broadly, RTI‐13951‐33 represents a unique tool to better understand GPR88 function, disentangle receptor roles in development from those in the adult and perhaps address other neuropsychiatric disorders.

Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation

“…10−12,16−18,23−25 RTI-13951-33 is the first-generation in vivo active agonist that has been shown to reduce alcohol drinking and seeking behaviors in mice and rats. 11,13 In the study presented here, we have conducted a lead optimization to further improve the potency and PK profile of RTI-13951-33. Our medicinal chemistry efforts led to the identification of RTI-122 (30a) that has EC 50 values of 11 and 12 nM in the cell-based cAMP accumulation and [ 35 S]GTPγS binding assays, respectively, and has GPR88-specific agonist activity in mouse striatal tissues.…”

“…Solvents used include EtOAc, hexanes, MeOH, and DCM. 1 H and 13 C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) or a Bruker AVANCE III HD 700 MHz spectrometer and were determined in CDCl 3 , DMSO-d 6 , or CD 3 OD with tetramethylsilane (TMS) (0.00 ppm) or solvent peaks as the internal reference. Chemical shifts are reported in parts per million relative to the reference signal, and coupling constant (J) values are reported in hertz.…”

“…The procedure for the synthesis of 5a was followed starting with (2S)-2-(4-bromophenyl)oxolane (4d, 94 mg) to afford 5d (128 mg, 53% yield) as a white foam: 1 (m, 1H), 1.43 (s, 9H), 1.39 (d, J = 8.9 Hz, 1H), 1.13 (d, J = 6.3 Hz, 3H); 13…”

“…The procedure for the synthesis of 6 was followed starting with 5f (40 mg) to afford 11 (35 mg, 95% yield) as a white solid: 1 (12). The procedure for the synthesis of 6 was followed starting with 5g (36 mg) to afford 12 (33 mg, 96% yield) as a white solid: 1 ( (13). The procedure for the synthesis of 6 was followed starting with 5h (40 mg) to afford 13 (37 mg, 98% yield) as a white solid: 1 (…”

“…NMR,13 C NMR, and HPLC data of selected compounds (PDF) Molecular formula strings with biological data (CSV) Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States; orcid.org/0000-0001-6733-3094; Phone: (919) 541-6328; Email: cjin@rti.org…”