title: Discovery of a dual action first-in-class peptide that mimics and enhances CNS-mediated actions of thyrotropin-releasing hormone.
abstract: Thyrotropin-releasing hormone (TRH) displays multiple CNS-mediated actions that have long been recognized to have therapeutic potential in treating a wide range of neurological disorders. Investigations of CNS functions and clinical use of TRH are hindered, however, due to its rapid degradation by TRH-degrading ectoenzyme (TRH-DE). We now report the discovery of a set of first-in-class compounds that display unique ability to both potently inhibit TRH-DE and bind to central TRH receptors with unparalleled affinity. This dual pharmacological activity within one molecular entity was found through selective manipulation of peptide stereochemistry. Notably, the lead compound of this set, L-pyroglutamyl-L-asparaginyl-L-prolyl-D-tyrosyl-D-tryptophan amide (Glp-Asn-Pro-D-Tyr-D-TrpNH(2)), is effective in vivo at producing and potentiating central actions of TRH without evoking release of thyroid-stimulating hormone (TSH). Specifically, this peptide displayed high plasma stability and combined potent inhibition of TRH-DE (K(i) 151 nM) with high affinity binding to central TRH receptors (K(i) 6.8 nM). Moreover, intraperitoneal injection of this peptide mimicked and augmented the effects of TRH on behavioural activity in rat. Analogous to TRH, it also antagonized pentobarbital-induced narcosis when administered intravenously. This discovery provides new opportunities for probing the role of TRH actions in the CNS and a basis for development of novel TRH-based neurotherapeutics.
authors.affiliation: School of Biochemistry and Immunology and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Gaia A
authors.initials: GA
authors.lastname: Scalabrino
authors.forename: Nicola
authors.initials: N
authors.lastname: Hogan
authors.forename: Kathy M
authors.initials: KM
authors.lastname: O'Boyle
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Slator
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gregg
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Fitchett
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Draper
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Bennett
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Hinkle
authors.forename: Karl
authors.initials: K
authors.lastname: Bauer
authors.forename: Carvell H
authors.initials: CH
authors.lastname: Williams
authors.forename: Keith F
authors.initials: KF
authors.lastname: Tipton
authors.forename: Julie A
authors.initials: JA
authors.lastname: Kelly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D003461:Crystallography / Q000379:methods; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000502:physiology; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone