Evaluation of Amide Bioisosteres Leading to 1,2,3-Triazole Containing Compounds as GPR88 Agonists: Design, Synthesis, and Structure–Activity Relationship Studies

Rahman, Toufiqur; Decker, Ann M.; Laudermilk, Lucas; Maitra, Rangan; Ma, Weiya; Hamida, Sami Ben; Darcq, Emmanuel; Kieffer, Brigitte L.; Jin, Chunyang

doi:10.1021/acs.jmedchem.1c01075

Cited by 23 publications

(34 citation statements)

References 48 publications

(168 reference statements)

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“…After reaching a stable baseline of responding, mice received saline or RTI-13951-33 (30 mg/kg, ip) 30 min before the 4-h alcohol self-administration session, using a within-subjects design (Weeks 14 and 15, Figure 3A). Total locomotor activity in the operant chamber was identical for saline-and RTI-13951-33-treated mice, suggesting that the GPR88 agonist did not impair mouse activity under our conditions (t [18] = 0.92, p = 0.36) (Figure 3B).…”

Section: Rti-13951-33 Reduces Alcohol Selfadministrationmentioning

confidence: 79%

“…13 We have pioneered the design, synthesis and study of a family of GPR88 agonists, starting from 2-PCCA 14,15 to novel series of brain-penetrant drugs with improved potency and efficacy. [16][17][18] In particular, RTI-13951-33, 16 the second-generation lead GPR88 agonist, shows nanomolar potency (EC 50 = 25 nM) at the recombinant receptor using an in vitro cAMP assay. Moreover, the compound efficiently stimulates GPR88-mediated G protein activity in striatal membranes prepared from control but not Gpr88 knockout mice, indicating activity and specificity at the native receptor.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Rti-13951-33 Reduces Alcohol Selfadministrationmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…We found that the two conditional lines together recapitulate the impulsivity-related de cits observed in the germ line Gpr88 knockout mice, making unlikely the possibility that the constitutive mutant phenotype is entirely due to early developmental compensatory mechanisms. In the future, the novel pharmacological tools under development may de nitely answer this question 10,49,50 .…”

Section: Gpr88 Regulates Impulsive Behaviorsmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Accurate SARs may be obtained by comprehensively comparing side chains without changing the scaffold, which is the central backbone of the original molecule. Some of the latest research to identify anticancer drugs, − psychiatric drugs, , antivirus drugs, , and even antibody–drug conjugates , are based on SARs, which represent an indispensable important research method.…”

Section: Introductionmentioning

confidence: 99%

Scaffold-Retained Structure Generator to Exhaustively Create Molecules in an Arbitrary Chemical Space

Kaitoh

Yamanishi

2022

J. Chem. Inf. Model.

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The construction of a virtual library (VL) consisting of novel molecules based on structure–activity relationships is crucial for lead optimization in rational drug design. In this study, we propose a novel scaffold-retained structure generator, EMPIRE (Exhaustive Molecular library Production In a scaffold-REtained manner), to create novel molecules in an arbitrary chemical space. By combining a deep learning model-based generator and a building block-based generator, the proposed method efficiently provides a VL consisting of molecules that retain the input scaffold and contain unique arbitrary substructures. The proposed method enables us to construct rational VLs located in unexplored chemical spaces containing molecules with unique skeletons (e.g., bicyclo[1.1.1]pentane and cubane) or elements (e.g., boron and silicon). We expect EMPIRE to contribute to efficient drug design with unique substructures by virtual screening.

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Evaluation of Amide Bioisosteres Leading to 1,2,3-Triazole Containing Compounds as GPR88 Agonists: Design, Synthesis, and Structure–Activity Relationship Studies

Cited by 23 publications

References 48 publications

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

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

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

Scaffold-Retained Structure Generator to Exhaustively Create Molecules in an Arbitrary Chemical Space

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