Engineering Galanin Analogues That Discriminate between GalR1 and GalR2 Receptor Subtypes and Exhibit Anticonvulsant Activity following Systemic Delivery

Robertson, Charles R.; Schöll, E; Pruess, Timothy H.; Green, Brad R.; White, H. Steve; Bułaj, Grzegorz

doi:10.1021/jm9018349

Cited by 35 publications

(54 citation statements)

References 19 publications

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“…Cationization and lipidization of galanin (1-13) provided two galanin analogues, Gal-B2 and [B-Me, des-Sar]Gal-B2, which are metabolically stable and CNS-penetrating. Both analogues are highly active in 6-Hz model of pharmacoresistant seizures upon systemic administration (30)(31)(32)(33). In addition, Gal-B2 is active in the Frings audiogenic seizure-susceptible mouse and in the corneal kindling model of partial epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…Much effort has been made in recent years toward development of systemically active agonists/ modulators for GalR1 and GalR2 receptors and, as of today, two nonpeptide, systemically active agonists, Galnon (17) and Galmic (29), and a CNSpenetrating peptide, galanin analogue Gal-B2 (30)(31)(32)(33), have been synthesized and characterized. All three galanin receptor agonists have been shown to exhibit potent anticonvulsant effect upon systemic application.…”

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confidence: 99%

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GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

Lü

Roberts

Xia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the 125 I galanin-binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM-2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target.galanin | seizure | G protein-coupled receptor | status epilepticus T he neuropeptide galanin (1) is widely expressed in the central nervous system (2-4), in which it regulates a variety of physiological and pathological processes, including pain, learning and memory, mood, addiction, and food intake (5-16). In addition, converging lines of evidence suggest a critical role for galanin in seizure control. Galanin has been shown to exhibit potent anticonvulsant effect in both acute and chronic seizure models in rodents. Intrahippocampally injected galanin strongly and irreversibly attenuated the status epilepticus (SE) induced by perforant path stimulation in rats (17). Mice with null mutation of galanin were more susceptible to develop SE after perforant path stimulation or systemic kainic acid injection, and exhibited more severe seizures following pentylenetetrazol injection (18). In contrast, mice that overexpress galanin under a dopamine-β-hydroxylase promoter had increased resistance to seizure induction in these three models (18). A separate line of transgenic mice that overexpress galanin under the plateletderived growth factor β promoter was found to exhibit delayed epileptogenesis induced by kindling stimulations (19). Moreover, galanin delivered to the rat brain via adenoassociated viral vectors has been shown to suppress kainic acid-induced seizures (20, 21), attenuate inferior collicular stimulation induced wild running seizure (21), and delay kindling development (22).The aforementioned anticonvulsant effects of galanin were most likely mediated through galanin receptor type 1 (GalR1) and type 2 (GalR2). GalR1-knockout mice exhibited spontaneous ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

Lü

Roberts

Xia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Early studies of the galaninergic system, including mutagenesis studies, mainly focused on the GalR1 subtype, wherefore GalR1 is the most well characterized entity of the three receptors. However, since the introduction of several subtype preferential ligands (Liu et al, 2001;Sollenberg et al, 2006;Konkel et al, 2006;Runesson et al, 2009a;Robertson et al, 2010) have the other receptor subtypes gained increased interest. To further delineate the galaninergic system, highly selective tools are needed.…”

Section: Discussionmentioning

confidence: 99%

Determining receptor–ligand interaction of human galanin receptor type 3

Runesson

Sollenberg

Jurkowski

et al. 2010

Neurochemistry International

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“…To design such NPW-derived compounds, we employed the lipidizationcationization strategy that was successfully applied toward systemically active analogues of GAL, NT, and NPY (GAL-B2, NT-BBB1, and NPY-BBB2, respectively)- (10,(20)(21)(22)(23). Structures and summary of anticonvulsant and physicochemical properties of GAL-B2, NT-BBB1 and NPY-BBB2 are provided in Figure S2 in the Supporting Information.…”

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confidence: 99%

“…Design of BBB-permeable NPW analogues was based on previous structure-activity relationship (SAR) findings that the C-terminal fragment NPW [14][15][16][17][18][19][20][21][22][23] and the N-terminal tripeptide of NPW are important for its structural and functional properties (24). Furthermore, Kanesaka and co-workers constructed centrally truncated analogues of NPW in which nonessential amino acid residues were replaced by backbone spacer units (5-aminovaleric acid), resulting in potent and selective NPWB 1 agonists (12).…”

mentioning

confidence: 99%

Analgesic Neuropeptide W Suppresses Seizures in the Brain Revealed by Rational Repositioning and Peptide Engineering

Green¹,

Smith²,

White³

et al. 2010

ACS Chem. Neurosci.

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Anticonvulsant neuropeptides play an important role in controlling neuronal excitability that leads to pain or seizures. Based on overlapping inhibitory mechanisms, many anticonvulsant compounds have been found to exhibit both analgesic and antiepileptic activities. An analgesic neuropeptide W (NPW) targets recently deorphanized G-protein coupled receptors. Here, we tested the hypothesis that the analgesic activity of NPW may lead to the discovery of its antiepileptic properties. Indeed, direct administration of NPW into the brain potently reduced seizures in mice. To confirm this discovery, we rationally designed, synthesized, and characterized NPW analogues that exhibited anticonvulsant activities following systemic administration. Our results suggest that the combination of neuropeptide repositioning and engineering NPW analogues that penetrate the blood-brain barrier could provide new drug leads, not only for the treatment of epilepsy and pain but also for studying effects of this peptide on regulating feeding and energy metabolism coupled to leptin levels in the brain.

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Engineering Galanin Analogues That Discriminate between GalR1 and GalR2 Receptor Subtypes and Exhibit Anticonvulsant Activity following Systemic Delivery

Cited by 35 publications

References 19 publications

GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

Determining receptor–ligand interaction of human galanin receptor type 3

Analgesic Neuropeptide W Suppresses Seizures in the Brain Revealed by Rational Repositioning and Peptide Engineering

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