Anticonvulsant activity of a nonpeptide galanin receptor agonist

Saar, Külliki; Mazarati, Andréy; Mahlapuu, Riina; Hallnemo, Gerd; Soomets, Ursel; Kilk, Kalle; Hellberg, Sven; Pooga, Margus; Tolf, Bo-Ragnar; Shi, Tie‐Jun Sten; Hökfelt, Tomas; Wasterlain, Claude G.; Bartfai, Tamás; Langel, Ülo

doi:10.1073/pnas.102163499

Cited by 123 publications

(120 citation statements)

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“…Galnon is a galanin agonist that is thought to have some selectivity for GalR1 over GalR2 and GalR3 (Saar et al, 2002;Wu et al, 2003). Galnon can act as a galanin receptor agonist in vivo in behavioral paradigms modulated by the endogenous peptide galanin, including opiate withdrawal (Zachariou et al, 2003), feeding behavior (Abramov et al, 2004), seizures (Saar et al, 2002), and anxiety (Rajarao et al, 2007). However, it should be noted that galnon can also interact directly with some G proteins (Flören et al, 2005), thus the action of galnon may not be limited to activation of GalR1.…”

Section: Discussionmentioning

confidence: 99%

“…On day 12, each mouse received an i.p. injection of 2 mg/kg galnon (synthesized as described in Saar et al, 2002) followed by an injection of 5 mg/kg morphine 15 min later. On day 13, injection of 2 mg/kg galnon was followed by an injection of saline 15 min later.…”

Section: Morphine-induced Locomotor Activationmentioning

confidence: 99%

“…Galnon, 7-((9-fluorenylmethoxycarbonyl)cyclohexylalanyllysyl)amino-4-methylcoumarin, is a low molecular weight, non-peptide galanin receptor agonist that displaces [ 125 I]glanin from its binding sites and inhibits adenylyl cyclase activity through activation of galanin receptors (Saar et al, 2002;Wu et al, 2003). Galnon administration reversed the morphine-induced increase in locomotor activation seen in GKO mice (F(7, 99) ¼ 6.513, po0.05; Figure 1b); however, galnon did not further reduce locomotor activity in WT mice and had no effect on its own (p40.05, Tukey HSD post hoc test).…”

Section: Morphine-induced Locomotor Activity and Cppmentioning

confidence: 99%

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Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

Neuropsychopharmacol

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The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.

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Section: Discussionmentioning

confidence: 99%

Section: Morphine-induced Locomotor Activationmentioning

confidence: 99%

Section: Morphine-induced Locomotor Activity and Cppmentioning

confidence: 99%

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Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

Neuropsychopharmacol

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“…Galanin‐KO mice exert a lowered threshold to seizures,4 and galanin antagonists exert proconvulsant effects,5 indicating a role of endogenous galanin in protecting from the expression of epileptic seizures. The anticonvulsive action of galanin may be mediated differently by galanin 1 receptor (GAL1‐R) and galanin 2 receptor (GAL2‐R).…”

Section: Introductionmentioning

confidence: 99%

Effects of galanin receptor 2 and receptor 3 knockout in mouse models of acute seizures

et al. 2018

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SummaryThere exists solid evidence that endogenous galanin and galanin agonists exert anticonvulsive actions mediated both by galanin 1 receptor (GAL1‐R) and galanin 2 receptor (GAL2‐R). We have now investigated whether depletion of the recently identified third galanin receptor, GAL3‐R, and that of GAL2‐R, alters the threshold to the systemically applied γ‐aminobutyric acid (GABA) antagonist pentylenetetrazole (PTZ) or to intrahippocampally administered kainic acid (KA). In neither model, GAL3‐KO mice differed in their latency to the first seizure, mean seizure duration, total number of seizures, or time spent in seizures compared to wild‐type controls. In addition, consistent with previous data, the response to PTZ was not altered in GAL2‐KO mice. In contrast, intrahippocampal KA resulted in a significantly increased number of seizures and time spent in seizures in GAL2‐KO mice, although the latency to the first seizure and the duration of individual seizures was not altered. These results are consistent with the previous data showing that GAL2‐R knockdown does not affect the number of perforant path stimulations required for initiating status epilepticus but significantly increases the seizure severity during the ongoing status. In conclusion, our data support a specific role of GAL2‐R but not of GAL3‐R in mediating the anticonvulsive actions of endogenous galanin.

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“…Nevertheless, peptides from a peptide library based on the pharmacophores were tested, and galnon was identified as a low molecular weight, systemically active galanin receptor agonist (Figure 2). It has a K d of 1 µmol/L, exhibits no selectivity among the three galanin receptor subtypes, but is peptidolytically stable with a half-life of approximately 60 minutes and crosses the BBB [40] . This compound exhibited a remarkable and dose-dependent efficacy as an anticonvulsant, and thus reinvigorated the search for low molecular weight agonists and later for PAMs of the galanin receptor.…”

Section: Wwwnaturecom/aps Bartfai T Et Almentioning

confidence: 99%

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

Bartfai

Wang

2013

Acta Pharmacol Sin

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The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABA A receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world's first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.

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Anticonvulsant activity of a nonpeptide galanin receptor agonist

Cited by 123 publications

References 28 publications

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Effects of galanin receptor 2 and receptor 3 knockout in mouse models of acute seizures

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

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