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Corticotropin releasing hormone - a GPCR drug target

Journal Article


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Abstract


  • Corticotrophin Releasing Hormone (CRH) is a primary hormone in the fight or flight response targeting a membrane bound G-protein coupled receptor (GPCR). Many people worldwide stand to benefit by the development of CRH agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimers, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR targeted therapeutic.

    Several key proteins influence the complex and intrinsic regulation of CRH, including its receptors (CRHR), of which 3 types have been categorised, CRHR1, CRHR2, CRHR3, each containing active and inactive splice variants. Additionally, the CRH binding protein (CRHBP) is believed to moderate the effects of CRH at the receptor, whether it is as a molecular mop, or a delivery vessel, or both, is still being investigated.

    Homology based receptor modelling is a technique that has only recently become available with the crystallisation of bovine rhodopsin (a GPCR),[1] and the application of this technique to the CRH receptors is still in the early stages of development. Therefore, the medicinal chemist has previously had to rely on ligand-based strategies, specifically, the development of pharmacophores. Thus, an extensive number of both CRH peptide analogues and small ligands that show nanomolar antagonism have been developed with SAR libraries being integral to the iterative drug design process.

Authors


  •   Hemley, Catherine (external author)
  •   McCluskey, Adam (external author)
  •   Keller, Paul A.

Publication Date


  • 2007

Citation


  • Hemley, C., McCluskey, A. & Keller, P. A. (2007). Corticotropin releasing hormone - a GPCR drug target. Current Drug Targets, 8 (1), 105-115.

Scopus Eid


  • 2-s2.0-33846002760

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1045&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/54

Number Of Pages


  • 10

Start Page


  • 105

End Page


  • 115

Volume


  • 8

Issue


  • 1

Place Of Publication


  • http://bentham.org/cdt/index.htm

Abstract


  • Corticotrophin Releasing Hormone (CRH) is a primary hormone in the fight or flight response targeting a membrane bound G-protein coupled receptor (GPCR). Many people worldwide stand to benefit by the development of CRH agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimers, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR targeted therapeutic.

    Several key proteins influence the complex and intrinsic regulation of CRH, including its receptors (CRHR), of which 3 types have been categorised, CRHR1, CRHR2, CRHR3, each containing active and inactive splice variants. Additionally, the CRH binding protein (CRHBP) is believed to moderate the effects of CRH at the receptor, whether it is as a molecular mop, or a delivery vessel, or both, is still being investigated.

    Homology based receptor modelling is a technique that has only recently become available with the crystallisation of bovine rhodopsin (a GPCR),[1] and the application of this technique to the CRH receptors is still in the early stages of development. Therefore, the medicinal chemist has previously had to rely on ligand-based strategies, specifically, the development of pharmacophores. Thus, an extensive number of both CRH peptide analogues and small ligands that show nanomolar antagonism have been developed with SAR libraries being integral to the iterative drug design process.

Authors


  •   Hemley, Catherine (external author)
  •   McCluskey, Adam (external author)
  •   Keller, Paul A.

Publication Date


  • 2007

Citation


  • Hemley, C., McCluskey, A. & Keller, P. A. (2007). Corticotropin releasing hormone - a GPCR drug target. Current Drug Targets, 8 (1), 105-115.

Scopus Eid


  • 2-s2.0-33846002760

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1045&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/54

Number Of Pages


  • 10

Start Page


  • 105

End Page


  • 115

Volume


  • 8

Issue


  • 1

Place Of Publication


  • http://bentham.org/cdt/index.htm