Discovery of a dual action first-in-class peptide that mimics and enhances CNS-mediated actions of thyrotropin-releasing hormone

Scalabrino, Gaia; Hogan, Nicola; O’Boyle, Kathy M.; Slator, Gillian R.; Gregg, Daniel J.; Fitchett, Christopher M.; Draper, Sylvia M.; Bennett, Gerald; Hinkle, Patricia M.; Bauer, Karl; Williams, C. H.; Tipton, Keith F.; Kelly, Julie

doi:10.1016/j.neuropharm.2007.02.003

Cited by 31 publications

(39 citation statements)

References 65 publications

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“…Previously-developed TRH analogs have not sufficiently overcome these impediments: structural features compromising receptor affinity and efficacy, as well as endocrine effects, remained (Scalabrino et al, 2007).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Our earlier studies identified JAK4D as the lead compound of a set of first-in-class neuropeptides that uniquely incorporate a dual-function pharmacophore for potent inhibition of TRH-DE (K i 151 nM) together with selectivity and potent affinity for central TRH receptors in rat brain (K i 6.8 nM) (Scalabrino et al, 2007). This compound is readily synthesized and chemically stable, displays high plasma stability, and is effective in mimicking and enhancing well-defined central behavioral actions of TRH in rat without evoking endocrine effects (Scalabrino et al, 2007).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…This compound is readily synthesized and chemically stable, displays high plasma stability, and is effective in mimicking and enhancing well-defined central behavioral actions of TRH in rat without evoking endocrine effects (Scalabrino et al, 2007). By overcoming the above mentioned limitations of native TRH and prior analogs, JAK4D presents an innovative means to selectively deliver the centrally-mediated therapeutic benefits of TRH in treating neurodegeneration and other CNS disorders.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Passage of JAK4D across the blood-brain-barrier (BBB) is favored by its greater lipophilicity compared to TRH (as reflected by respective retention times of 17 min and 9 min on reverse phase high pressure liquid chromatography (Scalabrino et al, 2007)). Moreover, passage is strongly indicated by the behavioral and neuropharmacological effects elicited by JAK4D ( (Scalabrino et al, 2007) and herein).…”

Section: Brain Permeationmentioning

confidence: 99%

“…While multifaceted intervention conceivably might be accomplished by a cocktail of targeted drugs, a single multifunctional therapeutic agent would be an attractive alternative. Herein we describe neuropharmacological evaluation of a first-in-class thyrotropin-releasing hormone (TRH)-based compound, hereafter designated JAK4D (Scalabrino et al, 2007) (US Pat. 7713935 B2), which offers such a multifaceted approach.…”

Section: Introductionmentioning

confidence: 99%

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First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

Kelly¹,

Boyle²,

Cole³

et al. 2015

Neuropharmacology

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Hardiman, O., First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models, Neuropharmacology (2014), doi: 10.1016/j.neuropharm.2014.09.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTABSTRACT JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain-barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Section: Brain Permeationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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