Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics

Zhang, Liuyin; Klein, Brian D.; Metcalf, Cameron S.; Smith, Michael L.; McDougle, Daniel R.; Lee, Hee Kyoung; White, H. Steve; Bułaj, Grzegorz

doi:10.1021/mp300236v

Cited by 9 publications

(17 citation statements)

References 84 publications

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“…Chemical synthesis of NAX 505-5 and NAX 409-9 was previously described (Bulaj et al, 2008;Zhang et al, 2013). Both analogs were synthesized by PolyPeptide Laboratories (San Diego, CA), and delivered as a lyophilized material (acetate salt, purity .95%).…”

Section: Methodsmentioning

confidence: 99%

“…This modified neuropeptide is a peripherally acting, GalR2-preferring galanin analog containing a C-terminal dPEG modification. We previously described the synthesis, galanin receptor binding, and effects obtained from pharmacologic screening of this compound (Zhang et al, 2013) in several assays.…”

Section: Methodsmentioning

confidence: 99%

“…The peptide was derived from the native galanin fragment, gal(1-16), with subsequent C-terminal dPEG modification. The chemical structure, synthesis, galanin receptor binding, and pharmacologic screening of this compound have been previously described (Zhang et al, 2013).…”

Section: Analgesic Pharmacologymentioning

confidence: 99%

“…Our prototype galanin analog, NAX 505-5, has demonstrated potent antiseizure activity in several animal models (White et al, 2009;Jequier Gygax et al, 2014). We have also recently shown that peptides containing monodisperse oligoethyleneglycol (dPEG) modifications, with minimal penetration into the central nervous system, effectively reduce pain-related behaviors in the formalin and carrageenan models of pain (Zhang et al, 2013). These dPEG modifications applied to neuropeptides like galanin provide potential first-in-class neurotherapeutics for pain.…”

Section: Introductionmentioning

confidence: 99%

“…These dPEG modifications applied to neuropeptides like galanin provide potential first-in-class neurotherapeutics for pain. In this work, we describe the further pharmacologic characterization and toxicity screening of a novel dPEG-containing GalR2-preferring analog, NAX 409-9 [referred to previously as Gal-R2-dPEG 24 (Zhang et al, 2013)]. These studies illustrate that this nonbrain-penetrating analog reduces pain behaviors in several animal models and does not show some of the dose-limiting toxicities associated with representative analgesics, including reduced gastrointestinal (GI) motility and respiratory depression for opiates and increased bleed time for NSAIDs.…”

Section: Introductionmentioning

confidence: 99%

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Analgesic Properties of a Peripherally Acting and GalR2 Receptor–Preferring Galanin Analog in Inflammatory, Neuropathic, and Acute Pain Models

Metcalf¹,

Klein

McDougle³

et al. 2014

J Pharmacol Exp Ther

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There are ongoing efforts to develop pain therapeutics with novel mechanisms of action that avoid common side effects associated with other analgesics. The anticonvulsant neuropeptide galanin is a potent regulator of neuronal excitability and has a well established role in pain modulation, making it a potential target for novel therapies. Our previous efforts focused on improving blood-brain-barrier penetration and enhancing the metabolic stability of galanin analogs to protect against seizures. More recently, we designed peripherally acting galanin analogs that reduce pain-related behaviors by acting in the periphery and exhibit preferential binding toward galanin receptor (GalR)2 over GalR1. In this study, we report preclinical studies of a monodisperse oligoethylene glycol-containing galanin analog, NAX 409-9 (previously reported as GalR2-dPEG 24 ), in rodent analgesic and safety models. Results obtained with NAX 409-9 in these tests were compared with the representative analgesics gabapentin, ibuprofen, acetylsalicylic acid, acetaminophen, and morphine. In mice that received intraplantar carrageenan, NAX 409-9 increased paw withdrawal latency with an ED 50 of 6.6 mg/kg i.p. NAX 409-9 also increased the paw withdrawal threshold to mechanical stimulation following partial sciatic nerve ligation in rats (2 mg/kg). Conversely, NAX 409-9 had no effect in the tail flick or hot plate assays (up to 24 mg/kg). Importantly, NAX 409-9 did not negatively affect gastrointestinal motility (4-20 mg/kg), respiratory rate (40-80 mg/kg), or bleed time (20 mg/kg). These studies illustrate that this nonbrain-penetrating galanin analog reduces pain behaviors in several models and does not produce some of the dose-limiting toxicities associated with other analgesics.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Analgesic Pharmacologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Analgesic Properties of a Peripherally Acting and GalR2 Receptor–Preferring Galanin Analog in Inflammatory, Neuropathic, and Acute Pain Models

Metcalf¹,

Klein

McDougle³

et al. 2014

J Pharmacol Exp Ther

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Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2

et al. 2017

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The potential clinical utility of galanin peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia. In addition to possessing potent anticonvulsant efficacy, galanin analogs are analgesic in various assays. The purpose of these studies was to evaluate the lead galanin receptor type 2 (GalR2)-preferring analog, NAX 810-2, in various pain assays, as well as determine any potential for insulin inhibition, growth hormone stimulation, and cognitive impairment. NAX 810-2 was evaluated in mouse (carrageenan, formalin, tail flick, plantar incision) and rat pain models (partial sciatic nerve ligation). NAX 810-2 dose-dependently increased paw withdrawal latency following plantar administration of carrageenan (ED50 4.7 mg/kg). At a dose of 8 mg/kg, NAX 810-2 significantly attenuated nociceptive behaviors following plantar administration of formalin, and this was observed for both phase I (acute) and phase II (inflammatory) components of the formalin behavioral response. NAX-810-2 was active at higher doses in the mouse tail flick model (ED50 20.2 mg/kg) and similarly, reduced mechanical allodynia following plantar incision in mice at a dose of 24 mg/kg. NAX 810-2 also reduced mechanical allodynia in the partial sciatic nerve ligation model at a dose of 4 mg/kg. In addition, NAX 810-2 did not impair insulin secretion at doses of 2.5 and 8 mg/kg (acutely) or at a dose of 8 mg/kg given daily for 5 days. Similarly, 8 mg/kg (twice daily, 5 days) of NAX 810-2 did not increase growth hormone levels. These results demonstrate that NAX 810-2 possesses a favorable pre-clinical profile as a novel and first-in-class analgesic.

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Ala 5 -galanin (2–11) is a GAL 2 R specific galanin analogue

et al. 2016

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It is over 30years since the regulatory peptide galanin was discovered by Professor Mutt and co-workers. Galanin exerts its effects by binding to three galanin G-protein coupled receptors, namely GALR, GALR and GALR. Each galanin receptor has a different distribution in the central nervous system and the peripheral nervous system as well as distinctive signaling pathways, which implicates that the receptors are involved in different biological- and pathological effects. The delineation of the galaninergic system is however difficult due to a lack of stable, specific galanin receptor ligands. Herein, a new short GALR specific ligand, Ala-galanin (2-11), is presented. The galanin (2-11) modified analogue Ala-galanin (2-11) was tested in I-galanin competitive binding studies for the three galanin receptors and the G-protein coupled receptor signaling properties was tested by the ability to influence second-messenger molecules like inositol phosphate and cyclic adenosine monophosphate. In addition, two different label-free real-time assays, namely EnSpire® based on an optical biosensor and xCELLigence® based on an electric biosensor, were used for evaluating the signaling properties using cell lines with different levels of receptor expression. Ala-galanin (2-11) was subsequently found to be a full agonist for GALR with more than 375-fold preference for GALR compared to both GALR and GALR. The single amino acid substitution of serine to alanine at position 5 in the short ligand galanin (2-11) resulted in a ligand subsequently unable to bind neither GALR nor GALR, even at concentrations as high as 0.1mM.

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Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics

Cited by 9 publications

References 84 publications

Analgesic Properties of a Peripherally Acting and GalR2 Receptor–Preferring Galanin Analog in Inflammatory, Neuropathic, and Acute Pain Models

Analgesic Properties of a Peripherally Acting and GalR2 Receptor–Preferring Galanin Analog in Inflammatory, Neuropathic, and Acute Pain Models

Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2

Ala 5 -galanin (2–11) is a GAL 2 R specific galanin analogue

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