Discovery of Selective Nonpeptidergic Neuropeptide FF2 Receptor Agonists

Gaubert, Gilles; Bertozzi, Fabio; Kelly, Nicholas M.; Pawlas, Jan; Scully, Audra L.; Nash, Norman R.; Gardell, Luis R.; Lameh, Jelveh; Olsson, Roger

doi:10.1021/jm9011998

Cited by 27 publications

(59 citation statements)

References 19 publications

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“…The novel small molecule, nonpeptidic NPFF ligands AC-262616, AC-263093, AC-262620, and AC-262970 were synthesized by ACADIA Pharmaceuticals. Further details pertaining to the chemical properties and structures of these compounds have been disclosed elsewhere (Gaubert et al, 2009). NPFF (FLFQPQRF-NH 2 ) and NPAF (AGEGLNSQFWSLAAPQRF-NH 2 ) were purchased from American Peptide Co., Inc. (Sunnyvale, CA) and Bachem Biosciences (King of Prussia, PA), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The lack of spinal FF1 receptors has led to the hypothesis that the antinociceptive actions of NPFF are mediated via FF2 receptors, whereas the pronociceptive actions of NPFF are mediated via FF1 receptors (Liu et al, 2001). We have identified several novel small molecule, nonpeptidic, ligands with varying degrees of functional selectivity for the NPFF receptor subtypes (Gaubert et al, 2009). The goal of this investigation was to use these pharmacological tools to define the roles of the NPFF receptors as they pertain to pain modulation.…”

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confidence: 99%

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Neuropeptide FF Receptors Have Opposing Modulatory Effects on Nociception

Lameh

Bertozzi²,

Kelly³

et al. 2010

J Pharmacol Exp Ther

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The role of neuropeptide FF (NPFF) and its analogs in pain modulation is ambiguous. Although NPFF was first characterized as an antiopioid peptide, both antinociceptive and pronociceptive effects have been reported, depending on the route of administration. Currently, two NPFF receptors, termed FF1 and FF2, have been identified and cloned, but their roles in pain modulation remain elusive because of the lack of availability of selective compounds suitable for systemic administration in in vivo models. Ligand-binding studies confirm ubiquitous expression of both subtypes in brain, whereas only FF2 receptors are expressed spinally. This disparity in localization has served as the foundation of the hypothesis that FF1 receptors mediate the pronociceptive actions of NPFF. We have identified novel small molecule NPFF receptor agonists and antagonists with varying degrees of FF2/FF1 functional selectivity. Using these pharmacological tools in vivo has allowed us to define the roles of NPFF receptor subtypes as pertains to the modulation of nociception. We demonstrate that selective FF2 agonism does not modulate acute pain but instead ameliorates inflammatory and neuropathic pains. Treatment with a nonselective FF1/FF2 agonist potentiates allodynia in neuropathic rats and increases sensitivity to noxious thermal and to non-noxious mechanical stimuli in normal rats in an FF1 antagonist-reversible manner. Treatment with FF1 antagonists reversed established mechanical allodynia, indicating the possibility of increased NPFF tone through FF1 receptors. In conclusion, we provide evidence for the opposing roles of NPFF receptors and highlight selective FF2 agonism and/or selective FF1 antagonism as potential targets warranting further investigation.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Neuropeptide FF Receptors Have Opposing Modulatory Effects on Nociception

Lameh

Bertozzi²,

Kelly³

et al. 2010

J Pharmacol Exp Ther

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“…Findeisen et al postulated that the length of the side chain is important, and that various molecular dynamics are responsible for formation of the agonist-receptor complex in the NPFF 1 R as compared with the NPFF 2 R [28]. The recently discovered selective NPFF 2 R agonist with a guanidinium group positioned very close to the core structure supports this hypothesis (compounds 1, 3 and 9; Table 10) [123]. These results are in agreement with the requirement of a long, charged side chain with hydrogen bonding potential at this position, suggesting that the specific role of the Arg is critical for best activation of both NPFF receptors.…”

Section: Physiological Effects Of Rfamide Peptidesmentioning

confidence: 98%

“…They demonstrated that systemic administration of the selective NPFF 2 R agonists (compound 1 and 3; Table 10) were active in various pain models in vivo , whereas administration of a nonselective NPFF 1 R and NPFF 2 R agonist (compound 9; Table 10) increases sensitivity to noxious and non-noxious stimuli [123]. …”

Section: Crosstalk/therapeutical Potentialmentioning

confidence: 99%

RFamide Peptides: Structure, Function, Mechanisms and Pharmaceutical Potential

2011

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Different neuropeptides, all containing a common carboxy-terminal RFamide sequence, have been characterized as ligands of the RFamide peptide receptor family. Currently, five subgroups have been characterized with respect to their N-terminal sequence and hence cover a wide pattern of biological functions, like important neuroendocrine, behavioral, sensory and automatic functions. The RFamide peptide receptor family represents a multiligand/multireceptor system, as many ligands are recognized by several GPCR subtypes within one family. Multireceptor systems are often susceptible to cross-reactions, as their numerous ligands are frequently closely related. In this review we focus on recent results in the field of structure-activity studies as well as mutational exploration of crucial positions within this GPCR system. The review summarizes the reported peptide analogs and recently developed small molecule ligands (agonists and antagonists) to highlight the current understanding of the pharmacophoric elements, required for affinity and activity at the receptor family. Furthermore, we address the biological functions of the ligands and give an overview on their involvement in physiological processes. We provide insights in the knowledge for the design of highly selective ligands for single receptor subtypes to minimize cross-talk and to eliminate effects from interactions within the GPCR system. This will support the drug development of members of the RFamide family.

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“…2-((1H-pyrrol-2-yl) methylene) hydrazine-1-carbothioamide (2) was designed and synthesized basing on 1H-pyrrole-2-carbaldehyde [1][2][3]. 2-((1-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)methylene)hydrazine-1-carboximidamid e(3) was synthesized according to 1-methyl-1H-pyrrole-2-carbaldehyde by Gilles Gaubert, Fabio Bertozzi et al [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 1-(2-(piperidin-1-yl)ethyl)-1H-pyrrole-2-carbaldehyde

Wang¹,

Tu²,

Han³

et al. 2017

Proceedings of the 2016 7th International Conference on Education, Management, Computer and Medicine (EMCM 2016)

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Abstract. 1-(2-(piperidin-1-yl)ethyl)-1H-pyrrole-2-carbaldehyde 4a-b is a new aqueous solubility aldehyde as an important intermediates of small molecule anticancer drugs. In this work, a rapid synthetic method for target compounds 4a-b was established. The compound 4a-b was synthesized from the commercially available pyrrole through three steps including acylation and two steps nucleophilic substitution. The structure was confirmed by MS and 1 HNMR. Furthermore, the synthetic method was optimized. The total yield of the three steps was 65%.

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Discovery of Selective Nonpeptidergic Neuropeptide FF2 Receptor Agonists

Cited by 27 publications

References 19 publications

Neuropeptide FF Receptors Have Opposing Modulatory Effects on Nociception

Neuropeptide FF Receptors Have Opposing Modulatory Effects on Nociception

RFamide Peptides: Structure, Function, Mechanisms and Pharmaceutical Potential

Synthesis of 1-(2-(piperidin-1-yl)ethyl)-1H-pyrrole-2-carbaldehyde

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