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Argininamide-type neuropeptide Y Y₁ receptor antagonists: the nature of N ^ω-carbamoyl substituents determines Y₁R binding mode and affinity.

ABSTRACT: The recently resolved crystal structure of the neuropeptide Y Y₁ receptor (Y₁R), co-crystallized with the high-affinity (pK _i: 10.11), argininamide-type Y₁R antagonist UR-MK299 (2), revealed that the N ^ω-carbamoyl substituent (van der Waals volume: 139 Å³) is deeply buried in the receptor, occupying a hydrophobic pocket. We synthesized and characterized a series of argininamides, structurally related to 2. Y₁R affinity decreased with increasing size of the carbamoyl residue (minimal pK _i: 5.67). Exceeding a critical size of the substituent (van der Waals volume: 212 Å³), the ligands bound in an inverted mode with the carbamoyl side chain located at the surface of the receptor, as suggested by induced-fit docking and MD simulations.

SUBMITTER: Buschmann J

PROVIDER: S-EPMC7536821 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Argininamide-type neuropeptide Y Y1 receptor antagonists: the nature of N ω-carbamoyl substituents determines Y1R binding mode and affinity.

Buschmann Jonas J Seiler Theresa T Bernhardt Günther G Keller Max M Wifling David D

RSC medicinal chemistry 20200120 2

The recently resolved crystal structure of the neuropeptide Y Y1 receptor (Y1R), co-crystallized with the high-affinity (pK i: 10.11), argininamide-type Y1R antagonist UR-MK299 (2), revealed that the N ω-carbamoyl substituent (van der Waals volume: 139 Å3) is deeply buried in the receptor, occupying a hydrophobic pocket. We synthesized and characterized a series of argininamides, structurally related to 2</ ...[more]

PMID: 33479634

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Project description:The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (Ki) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen's d = 2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen's d = 1.77) and raclopride (adjusted p = 0.052, Cohen's d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased Ki in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced Ki in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in Ki in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower Ki than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in Ki induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a nonselective D2/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.

Dataset Information

Argininamide-type neuropeptide Y Y₁ receptor antagonists: the nature of N ^ω-carbamoyl substituents determines Y₁R binding mode and affinity.

Publications

Argininamide-type neuropeptide Y Y<sub>1</sub> receptor antagonists: the nature of <i>N</i> <sup>ω</sup>-carbamoyl substituents determines Y<sub>1</sub>R binding mode and affinity.

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