Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor

Dvorak, Curt A.; Coate, Heather; Nepomuceno, Diane; Wennerholm, Michelle; Kuei, Chester; Lord, Brian; Woody, David; Bonaventure, Pascal; Liu, Changlu; Lovenberg, Timothy W.; Carruthers, Nicholas I.

doi:10.1021/acsmedchemlett.5b00247

Cited by 28 publications

(49 citation statements)

References 11 publications

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“…Other Phe and Trp derivatives were purchased from PepTech Corporation (Bedford, MA). JNJ-63533054 and JNJ-63770044 were synthesized at Janssen Research & Development, LLC (San Diego, CA) as described in Dvorak et al (2015). Molecular Cloning of GPR139 from Different Species.…”

Section: Methodsmentioning

confidence: 99%

“…A focused high-throughput screen for GPR139 was completed from a library of 100,000 compounds (small molecules, diversity set), and agonist leads were identified (Dvorak et al, 2015). Structure-activity relationship studies identified JNJ-63533054 (Fig.…”

Section: Gpr139 Receptor Activity In Recombinant Cellsmentioning

confidence: 99%

“…The small-molecule JNJ-63533054 was found to be devoid of any cross-reactivity as judged by an external selectivity panel of 50 known GPCRs, ion channels, and transporters, and it displayed suitable pharmacokinetic properties for in vivo studies (Dvorak et al, 2015). Information on the selectivity and pharmacokinetics of the GPR139 surrogate agonists previously published (TCO-9311 and LP-360924) are limited compared with those of JNJ-63533054.…”

Section: Gpr139 Is Activated By L-tryptophan and L-phenylalaninementioning

confidence: 99%

“…TCO 9311 was found to be a P-glycoprotein substrate with very limited ability to cross the blood-brain barrier (Shi et al, 2011). In contrast, JNJ-63533054 crosses the rat blood-brain barrier after oral administration and achieves exposure in the micromolar range (Dvorak et al, 2015). Structurally, JNJ-63533054 possesses functional group elements that can be found in the reported hydrazinecarboxamide agonist (TCO-9311) (Shi et al, 2011) having two carbonyls in a 1,4 relationship, separated by two atoms and accompanied by a large flanking hydrophobic surface.…”

Section: Gpr139 Is Activated By L-tryptophan and L-phenylalaninementioning

confidence: 99%

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GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids l-Tryptophan and l-Phenylalanine

et al. 2015

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GPR139 is an orphan G-protein-coupled receptor expressed in the central nervous system. To identify its physiologic ligand, we measured GPR139 receptor activity from recombinant cells after treatment with amino acids, orphan ligands, serum, and tissue extracts. GPR139 activity was measured using guanosine 59-O-(3-[ Sequence alignment revealed that GPR139 is highly conserved across species, and RNA sequencing studies of rat and human tissues indicated its exclusive expression in the brain and pituitary gland. Immunohistochemical analysis showed specific expression of the receptor in circumventricular regions of the habenula and septum in mice. Together, these findings suggest that L-Trp and L-Phe are candidate physiologic ligands for GPR139, and we hypothesize that this receptor may act as a sensor to detect dynamic changes of L-Trp and L-Phe in the brain.

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Section: Methodsmentioning

confidence: 99%

Section: Gpr139 Receptor Activity In Recombinant Cellsmentioning

confidence: 99%

Section: Gpr139 Is Activated By L-tryptophan and L-phenylalaninementioning

confidence: 99%

Section: Gpr139 Is Activated By L-tryptophan and L-phenylalaninementioning

confidence: 99%

See 2 more Smart Citations

GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids l-Tryptophan and l-Phenylalanine

et al. 2015

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“…from Lundbeck A/S11, Dvorak et al . from Jansen R&D1314, and Hitchcock et al . from Takeda Pharmaceutical Company Limited15.…”

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confidence: 99%

Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

Shehata

Nøhr

Lissa

et al. 2016

Sci Rep

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GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson’s disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization.

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Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors

Wang

Lee

Shih

et al. 2019

Pharmacology Res & Perspec

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GPR139 is a Gq‐coupled receptor activated by the essential amino acids L‐tryptophan (L‐Trp) and L‐phenylalanine (L‐Phe). We carried out mutagenesis studies of the human GPR139 receptor to identify the critical structural motifs required for GPR139 activation. We applied site‐directed and high throughput random mutagenesis approaches using a double addition normalization strategy to identify novel GPR139 sequences coding receptors that have altered sensitivity to endogenous ligands. This approach resulted in GPR139 clones with gain‐of‐function, reduction‐of‐function or loss‐of‐function mutations. The agonist pharmacology of these mutant receptors was characterized and compared to wild‐type receptor using calcium mobilization, radioligand binding, and protein expression assays. The structure‐activity data were incorporated into a homology model which highlights that many of the gain‐of‐function mutations are either in or immediately adjacent to the purported orthosteric ligand binding site, whereas the loss‐of‐function mutations were largely in the intracellular G‐protein binding area or were disrupters of the helix integrity. There were also some reduction‐of‐function mutations in the orthosteric ligand binding site. These findings may not only facilitate the rational design of novel agonists and antagonists of GPR139, but also may guide the design of transgenic animal models to study the physiological function of GPR139.

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Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor

Cited by 28 publications

References 11 publications

GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids l-Tryptophan and l-Phenylalanine

GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids l-Tryptophan and l-Phenylalanine

Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors

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